NM_023067.4:c.469C>G (p.Pro157Ala) is a missense variant in the forkhead DNA-binding domain of FOXL2.1 This variant is extremely rare in population databases (gnomAD v2.1: 1/203,794 alleles, AF=4.9e-06; v4.1: 9/1,589,638 alleles, AF=5.66e-06), meeting PM2 at supporting strength.2 Pro157 resides within the forkhead domain, a critical and well-established functional domain required for FOXL2 DNA-binding and transcriptional activity, meeting PM1 at supporting strength. Multiple computational predictors do not support a deleterious effect: REVEL score 0.291 (below pathogenic threshold), BayesDel score -0.188 (predicted benign), and SpliceAI max delta 0.00, meeting BP4 at supporting benign strength.3 This variant has been observed in somatic cancers (COSMIC: n=6) but lacks germline pathogenicity evidence. It is absent from ClinVar and no publications have directly characterized p.Pro157Ala.4 The evidence profile includes two pathogenic supporting criteria (PM1, PM2) and one benign supporting criterion (BP4), resulting in an indeterminate classification (Variant of Uncertain Significance) under the generic ACMG/AMP 2015 framework.5
FOXL2
Final classification
VUS
FOXL2 c.469C>G · p.Pro157Ala
FOXL2
NM_023067.4:c.469C>G (p.Pro157Ala) is a missense variant in the forkhead DNA-binding domain of FOXL2.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 supporting, PM2 supporting, BP4 supporting benign; combination = 2 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM1PM2
BP4
VUS
FOXL2 c.469C>G
PM1 + PM2 + BP4
→
VUS
3
revelbayesdelspliceai ↗
5
generic_acmg_combination_rules
Gene diagram
· NM_023067.4 · variants mapped to exon structure
FOXL2
NM_023067.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 20 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM1
supporting
review
Pathogenic
Located at codon 157 within the forkhead DNA-binding domain of FOXL2 (approximately residues 152–256), a critical and well-established functional domain required for transcription factor activity. Population data show extreme constraint (gnomAD AF ~5e-06), consistent with absence of benign variation in this domain. Residue-specific hotspot not identified at cancerhotspots.org, but domain-level application is supported.
FOXL2 forkhead domain is a well-characterized functional domain critical for DNA binding and transcriptional regulationPro157 is positioned at the N-terminal region of the forkhead domaingnomAD extreme constraint: v2.1 AF=4.9e-06
✓
PM2
supporting
Pathogenic
Extremely low allele frequency in population databases, well below the 0.1% PM2 threshold. gnomAD v2.1: 1/203,794 alleles (AF=4.9e-06); gnomAD v4.1: 9/1,589,638 alleles (AF=5.66e-06); absent from gnomAD-Canada v1.0. No homozygotes observed.
gnomAD v2.1: AF=4.9e-061/203794 alleles
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no significant impact. REVEL score 0.291 (below 0.5 pathogenic threshold), BayesDel score -0.188 (predicted benign), and SpliceAI max delta 0.00 (no splicing impact). HCI prior not available.
REVEL: 0.291 (below 0.5 threshold)BayesDel: -0.188 (negativepredicts benign)
Assessed · not applied
Pathogenic
PS1
No previously established pathogenic variant at this amino acid position (Pro157) has been identified in ClinVar or the literature.
PS2
No de novo occurrence data available for this variant.
PS3
No variant-specific functional studies identified.
PS4
No case-control or prevalence data comparing affected individuals to controls for this variant is available.
PM5
No pathogenic missense variant at the same codon (Pro157) identified in ClinVar or literature.
PM6
No de novo status confirmed for this variant.
PP1
No co-segregation data available for this variant.
PP2
FOXL2 missense variants are a known mechanism for blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) and premature ovarian insufficiency.
PP3
Multiple computational predictors do not support a deleterious effect.
PP4
No patient phenotype or family history data available in the case record to evaluate phenotype specificity for FOXL2-related disorders.
PP5
This variant is absent from ClinVar; no reputable source has classified it as pathogenic.
Benign
BA1
gnomAD allele frequency is far below the 1% BA1 threshold.
BS1
gnomAD allele frequency is far below the 0.3% BS1 threshold.
BS2
No evidence of this variant being observed in healthy adults with complete penetrance for a dominant disorder.
BS3
No well-established functional studies demonstrating no damaging effect for this variant.
BS4
No segregation data available to evaluate lack of segregation with disease.
BP1
FOXL2-related disease (BPES, POI) is known to be caused by missense variants; this is not a gene where only truncating variants cause disease.
BP2
No evidence of this variant observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant for a recessive disorder.
BP5
No alternate molecular basis for disease has been identified in the case record.
BP6
This variant is absent from ClinVar; no reputable source has classified it as benign.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 5.66167e-06; MAF= 0.00057%, 9/1589638 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.34112e-05; MAF= 0.00534%, 3/56168 alleles, homozygotes = 0); grpmax FAF= 1.417e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 4.90692e-06; MAF= 0.00049%, 1/203794 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.14563e-05; MAF= 0.00115%, 1/87288 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00057%
· 9 / 1,589,638
0 hom · FAF 0.0014%
0 hom · FAF 0.0014%
Admixed American 3 / 56,168 |
0.0053% |
African/African American 2 / 74,216 |
0.0027% |
Remaining individuals 1 / 61,518 |
0.0016% |
European (non-Finnish) 3 / 1,169,148 |
0.00026% |
+ 6 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.00049%
· 1 / 203,794
0 hom
0 hom
European (non-Finnish) 1 / 87,288 |
0.0011% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.291. BayesDel score = -0.188397.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FOXL2, a transcription factor, is recurrently mutated in adult granulosa cell tumors.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57730775, n = 6 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links