Is FOXE1 p.Ala172= (c.516C>A) pathogenic?

FOXE1 p.Ala172= (c.516C>A) is classified Benign/Likely benign in FOXE1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-05-12). Common (popmax 12.8%, afr) — too common for a highly-penetrant pathogenic allele.

FOXE1 p.Ala172=

Q: How common is FOXE1 p.Ala172= (c.516C>A) in the general population?

FOXE1 p.Ala172= (c.516C>A) is common (popmax 12.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.516C>A · rs775448711 · VCV1177758

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 12.8%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.9	GERP -3.5
Overall
CADD	5.03	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12.8% African / African-American · 8,056/63,076 alleles

Filtering AF 12.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.4%

Overall 3.42% 42,336/1,239,514 alleles · common exomes 33,948/1,092,934 · genomes 8,388/146,580 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	16%	6
African / African-Americangrpmax	12.8%	8
Middle Eastern	7.87%	13
Remaining individualsnot grpmax-eligible	4.75%	21
East Asian	3.93%	25
South Asian	3.51%	28
Admixed American	3.44%	29
European (non-Finnish)	2.61%	38
Amishnot grpmax-eligible	2.33%	43
Finnishnot grpmax-eligible	0.72%	139

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FOXE1
Protein: p.Ala172=
Coding: c.516C>A
MANE Select: NM_004473
dbSNP: rs775448711
Type: single nucleotide variant
Location: chr9:97854430 (GRCh38)
Gene constraint: LOEUF 1.926 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 62.02

Full FOXE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FOXE1 p.Ala118Val Uncertain significance ★★ ⚠ same type
FOXE1 p.Ala206Thr Uncertain significance ★★ ⚠ same type
FOXE1 p.Arg51Gly Uncertain significance ★★ ⚠ same type
FOXE1 p.Gly334Ala Uncertain significance ★★ ⚠ same type
FOXE1 p.Leu205Val Uncertain significance ★★ ⚠ same type
FOXE1 p.Ser294Asn Uncertain significance ★★ ⚠ same type
FOXE1 c.-131G>C Benign ★★ same type
FOXE1 c.-156T>C Benign ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/foxe1-p-ala172 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown