Is FOXE1 p.Pro203Arg (c.608C>G) pathogenic?

FOXE1 p.Pro203Arg (c.608C>G) is classified Uncertain significance in FOXE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). AlphaMissense: likely benign (0.2132); Low-frequency (popmax 1.68%, amr); Associated with thyroid cancer, nonmedullary, 4.

What condition is associated with FOXE1 p.Pro203Arg (c.608C>G)?

FOXE1 p.Pro203Arg (c.608C>G) is associated with thyroid cancer, nonmedullary, 4, Bamforth-Lazarus syndrome (ClinVar).

How common is FOXE1 p.Pro203Arg (c.608C>G) in the general population?

FOXE1 p.Pro203Arg (c.608C>G) is low-frequency (popmax 1.68%, amr) (gnomAD).

What do computational predictors say about FOXE1 p.Pro203Arg (c.608C>G)?

AlphaMissense predicts likely benign (score 0.2132) — an in-silico prediction, not a clinical call.

FOXE1 p.Pro203Arg

Q: How is Familial papillary or follicular thyroid carcinoma inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

c.608C>G · VCV3596018

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2132 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.68%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thyroid cancer, nonmedullary, 4

Computational evidence

Protein change
AlphaMissense	0.2132	likely benign
REVEL	0.196	benign-leaning
SaProt	LLR -7.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP 1.1, phastCons 0.43
Regional constraint	o/e 1.10	unconstrained · MANE · 555 bp · p 0.1 · regional, not allelic
Overall
CADD	18.71	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.68% Admixed American · 389/23,136 alleles

Filtering AF 1.54% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.49%

Overall 0.0347% 435/1,253,372 alleles · low-frequency exomes 191/1,102,224 · genomes 244/151,148 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	1.68%	59
Remaining individualsnot grpmax-eligible	0.0562%	1,779
African / African-American	0.0282%	3,543
European (non-Finnish)	0.000199%	501,645

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.Pro203Arg
Coding: c.608C>G
MANE Select: NM_004473
Type: single nucleotide variant
Location: chr9:97854522 (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

Disease context

thyroid cancer, nonmedullary, 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Bamforth-Lazarus syndrome

For Familial papillary or follicular thyroid carcinoma (Orphanet):

Inheritance: Not applicable
Onset: Adult

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.Arg116Ser Likely pathogenic ★ 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

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-pro203arg (accessed [today's date]).

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