Is TBX5 p.Ile320Phe (c.958A>T) pathogenic?

TBX5 p.Ile320Phe (c.958A>T) is classified Uncertain significance in TBX5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-08). AlphaMissense: likely benign (0.099); Very rare (popmax 0.000424%, nfe); Associated with aortic valve disease 2.

What condition is associated with TBX5 p.Ile320Phe (c.958A>T)?

TBX5 p.Ile320Phe (c.958A>T) is associated with aortic valve disease 2 (ClinVar).

How common is TBX5 p.Ile320Phe (c.958A>T) in the general population?

TBX5 p.Ile320Phe (c.958A>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about TBX5 p.Ile320Phe (c.958A>T)?

AlphaMissense predicts likely benign (score 0.099) — an in-silico prediction, not a clinical call.

TBX5 p.Ile320Phe

c.958A>T · rs1167784513 · VCV1767464

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.099 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

aortic valve disease 2

Computational evidence

Protein change
AlphaMissense	0.099	likely benign
REVEL	0.328	indeterminate
SaProt	LLR -5.86	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -2.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.52 · regional, not allelic
Overall
CADD	16.24	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 0.000424% European (non-Finnish) · 5/1,180,018 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,114 alleles · very rare exomes 5/1,461,874 · genomes 0/152,240 · 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: TBX5
Protein: p.Ile320Phe
Coding: c.958A>T
MANE Select: NM_181486
dbSNP: rs1167784513
Type: single nucleotide variant
Location: chr12:114366189 (GRCh38)
Gene constraint: LOEUF 0.267 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.38 · 4 PDB
Residue 320: the 'disordered' region

Full TBX5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

aortic valve disease 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TBX5 p.Ile320fs Pathogenic ★ same residue
TBX5 c.148-2A>G Pathogenic ★★ same condition
TBX5 c.243-1G>A Pathogenic/Likely pathogenic ★★ same condition
TBX5 c.362+2T>C Pathogenic/Likely pathogenic ★★ same condition
TBX5 c.756-2A>G Pathogenic/Likely pathogenic ★★ same condition
TBX5 c.982+1G>A Pathogenic/Likely pathogenic ★★ same condition
TBX5 c.982+2T>G Pathogenic/Likely pathogenic ★★ same condition
TBX5 p.Arg237Gln Pathogenic/Likely pathogenic ★★ 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/tbx5-p-ile320phe (accessed [today's date]).

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