Is TEAD4 p.Ala166Val (c.497C>T) pathogenic?

TEAD4 p.Ala166Val (c.497C>T) is classified Uncertain significance in TEAD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-14). AlphaMissense: likely benign (0.0831); Very rare (popmax 0.00347%, nfe).

How common is TEAD4 p.Ala166Val (c.497C>T) in the general population?

TEAD4 p.Ala166Val (c.497C>T) is very rare (popmax 0.00347%, nfe) (gnomAD).

What do computational predictors say about TEAD4 p.Ala166Val (c.497C>T)?

AlphaMissense predicts likely benign (score 0.0831) — an in-silico prediction, not a clinical call.

TEAD4 p.Ala166Val

c.497C>T · VCV3454560

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0831 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00347%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0831	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -7.41	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 3.2	GERP 1.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 46 kb · p 0.0017 · regional, not allelic
Overall
CADD	23.9	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 0.00347% European (non-Finnish) · 41/1,179,994 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00266% 43/1,613,990 alleles · very rare exomes 37/1,461,822 · genomes 6/152,168 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00347%	28,780
Admixed American	0.00333%	29,997

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.Ala166Val
Coding: c.497C>T
MANE Select: NM_003213
Type: single nucleotide variant
Location: chr12:3018558 (GRCh38)
Gene constraint: LOEUF 0.889 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.75 · 23 PDB

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.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
TEAD4 p.Arg108Cys 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-ala166val (accessed [today's date]).

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