Is FOXE1 p.Arg102Cys (c.304C>T) pathogenic?

FOXE1 p.Arg102Cys (c.304C>T) is classified Pathogenic in FOXE1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2011-03-01). AlphaMissense: likely pathogenic (0.9999); Very rare (popmax 0.00134%, afr); Associated with Bamforth-Lazarus syndrome.

What condition is associated with FOXE1 p.Arg102Cys (c.304C>T)?

FOXE1 p.Arg102Cys (c.304C>T) is associated with Bamforth-Lazarus syndrome (ClinVar).

How common is FOXE1 p.Arg102Cys (c.304C>T) in the general population?

FOXE1 p.Arg102Cys (c.304C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about FOXE1 p.Arg102Cys (c.304C>T)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

FOXE1 p.Arg102Cys

c.304C>T · rs104894111 · VCV6988

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bamforth-Lazarus syndrome

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic ✓ concordant with ClinVar · top 5% in FOXE1
REVEL	0.925	moderately pathogenic-leaning
SaProt	LLR -15.84	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 1.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 518 bp · p 0.21 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,882 alleles

Overall 6.2e-05% 1/1,613,146 alleles · very rare exomes 0/1,461,218 · genomes 1/151,928 · joint denominator

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.Arg102Cys
Coding: c.304C>T
MANE Select: NM_004473
dbSNP: rs104894111
Type: single nucleotide variant
Location: chr9:97854218 (GRCh38)
Gene constraint: LOEUF 1.926 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 62.02
Residue 102: a DNA-binding region; a UniProt-annotated variant site (in congenital hypothyroidism; with absence of thyroid agenesis; loss of sequence-specific dna binding; loss of transcriptional activity)

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

Disease context

Bamforth-Lazarus syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FOXE1 p.Ala118Val Uncertain significance ★★ ⚠ same condition
FOXE1 p.Leu129= Benign ★★ same condition
FOXE1 p.Lys95= Benign/Likely benign ★★ same condition
FOXE1 p.Ser275= Benign ★★ same condition
FOXE1 p.Ala168Thr Uncertain significance ★ ⚠ same condition
FOXE1 p.Ala178Val Uncertain significance ★ ⚠ same condition
FOXE1 p.Ala248Gly Conflicting classifications of pathogenicity ★ ⚠ same condition
FOXE1 p.Glu85Ter Uncertain significance ★ same condition

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-arg102cys (accessed [today's date]).

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