Is TRIP4 p.Val326Phe (c.976G>T) pathogenic?

TRIP4 p.Val326Phe (c.976G>T) is classified Uncertain significance in TRIP4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-14). AlphaMissense: likely benign (0.1462); Ultra-rare (popmax 0.0369%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TRIP4 p.Val326Phe (c.976G>T)?

TRIP4 p.Val326Phe (c.976G>T) is associated with Inborn genetic diseases (ClinVar).

How common is TRIP4 p.Val326Phe (c.976G>T) in the general population?

TRIP4 p.Val326Phe (c.976G>T) is ultra-rare (popmax 0.0369%, nfe) (gnomAD).

What do computational predictors say about TRIP4 p.Val326Phe (c.976G>T)?

AlphaMissense predicts likely benign (score 0.1462) — an in-silico prediction, not a clinical call.

TRIP4 p.Val326Phe

c.976G>T · rs149432140 · VCV546757

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1462 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0369%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1462	likely benign
REVEL	0.19	benign-leaning
SaProt	LLR -9.41	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 1.2	GERP -3.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 67 kb · p 0.41 · regional, not allelic
Overall
CADD	16.42	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 0.0369% European (non-Finnish) · 435/1,180,038 alleles

Filtering AF 0.034% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0328%

Overall 0.0285% 460/1,614,152 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0369%	2,713
Remaining individualsnot grpmax-eligible	0.0272%	3,677
Admixed American	0.00667%	15,003
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
African / African-American	0.00267%	37,516
East Asian	0.00223%	44,882

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: TRIP4
Protein: p.Val326Phe
Coding: c.976G>T
MANE Select: NM_016213
dbSNP: rs149432140
Type: single nucleotide variant
Location: chr15:64409761 (GRCh38)
Gene constraint: LOEUF 0.802 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.54 · 10 PDB
Residue 326: the 'mediates interaction with ufl1' region

Full TRIP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRIP4 p.Ala398Thr Uncertain significance ★★ ⚠ same condition
TRIP4 p.Arg104Gln Uncertain significance ★★ ⚠ same condition
TRIP4 p.Arg189Cys Uncertain significance ★★ ⚠ same condition
TRIP4 p.Arg321Gln Uncertain significance ★★ ⚠ same condition
TRIP4 p.Arg492Cys Uncertain significance ★★ ⚠ same condition
TRIP4 p.Asp100Asn Uncertain significance ★★ ⚠ same condition
TRIP4 p.Asp501Glu Uncertain significance ★★ ⚠ same condition
TRIP4 p.Gln441Leu Uncertain significance ★★ ⚠ 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/trip4-p-val326phe (accessed [today's date]).

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