Is FOXE1 p.Arg116Ser (c.346C>A) pathogenic?

FOXE1 p.Arg116Ser (c.346C>A) is classified Likely pathogenic in FOXE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-22). AlphaMissense: likely pathogenic (0.9993); Very rare (popmax 0.0011%, sas); Associated with thyroid cancer, nonmedullary, 4.

What condition is associated with FOXE1 p.Arg116Ser (c.346C>A)?

FOXE1 p.Arg116Ser (c.346C>A) is associated with thyroid cancer, nonmedullary, 4 (ClinVar).

How common is FOXE1 p.Arg116Ser (c.346C>A) in the general population?

FOXE1 p.Arg116Ser (c.346C>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about FOXE1 p.Arg116Ser (c.346C>A)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

FOXE1 p.Arg116Ser

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.346C>A · VCV3362432

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thyroid cancer, nonmedullary, 4

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic ✓ concordant with ClinVar · top 5% in FOXE1
REVEL	0.918	moderately pathogenic-leaning
SaProt	LLR -13.66	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 2.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 518 bp · p 0.21 · regional, not allelic
Overall
CADD	33.0	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 0.0011% South Asian · 1/91,044 alleles

Overall 6.84e-05% 1/1,460,974 alleles · very rare

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.Arg116Ser
Coding: c.346C>A
MANE Select: NM_004473
Type: single nucleotide variant
Location: chr9:97854260 (GRCh38)
Gene constraint: LOEUF 1.926 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 62.02
Residue 116: a DNA-binding region

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

For Familial papillary or follicular thyroid carcinoma (Orphanet):

Inheritance: Not applicable
Onset: Adult

Similar variants

FOXE1 p.Ala248Gly Conflicting classifications of pathogenicity ★ ⚠ same condition
FOXE1 p.Lys95Gln Uncertain significance ★ ⚠ same condition
FOXE1 p.Pro203Arg Uncertain significance ★ ⚠ same condition
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

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-arg116ser (accessed [today's date]).

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