Is TEAD4 p.Ser331Phe (c.992C>T) pathogenic?

TEAD4 p.Ser331Phe (c.992C>T) is classified Uncertain significance in TEAD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-22). AlphaMissense: likely pathogenic (0.9393); Very rare (popmax 0.005%, amr).

How common is TEAD4 p.Ser331Phe (c.992C>T) in the general population?

TEAD4 p.Ser331Phe (c.992C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about TEAD4 p.Ser331Phe (c.992C>T)?

AlphaMissense predicts likely pathogenic (score 0.9393) — an in-silico prediction, not a clinical call.

TEAD4 p.Ser331Phe

c.992C>T · VCV4182087

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9393 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9393	likely pathogenic
REVEL	0.765	pathogenic-leaning
SaProt	LLR -15.46	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 7.5	GERP 2.2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 46 kb · p 0.0017 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.005% Admixed American · 3/60,024 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00118% 19/1,613,968 alleles · very rare exomes 16/1,461,610 · genomes 3/152,358 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,008
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
European (non-Finnish)	0.00127%	78,658

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: TEAD4
Protein: p.Ser331Phe
Coding: c.992C>T
MANE Select: NM_003213
Type: single nucleotide variant
Location: chr12:3038062 (GRCh38)
Gene constraint: LOEUF 0.889 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.75 · 23 PDB
Residue 331: a β-strand

Full TEAD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TEAD4 p.Ala115Thr Uncertain significance ★ ⚠ same type
TEAD4 p.Ala136Val Uncertain significance ★ same type
TEAD4 p.Ala166Val Uncertain significance ★ ⚠ same type
TEAD4 p.Ala211Val Uncertain significance ★ ⚠ same type
TEAD4 p.Ala264Ser Uncertain significance ★ ⚠ same type
TEAD4 p.Ala30Ser Uncertain significance ★ ⚠ same type
TEAD4 p.Ala424Pro Uncertain significance ★ ⚠ same type
TEAD4 p.Ala56Thr 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/tead4-p-ser331phe (accessed [today's date]).

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