Is TRIP12 p.Val85Phe (c.253G>T) pathogenic?

TRIP12 p.Val85Phe (c.253G>T) is classified Uncertain significance in TRIP12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-17). AlphaMissense: likely benign (0.0804); Ultra-rare (popmax 0.0174%, afr); Associated with Inborn genetic diseases.

What condition is associated with TRIP12 p.Val85Phe (c.253G>T)?

TRIP12 p.Val85Phe (c.253G>T) is associated with Inborn genetic diseases (ClinVar).

How common is TRIP12 p.Val85Phe (c.253G>T) in the general population?

TRIP12 p.Val85Phe (c.253G>T) is ultra-rare (popmax 0.0174%, afr) (gnomAD).

What do computational predictors say about TRIP12 p.Val85Phe (c.253G>T)?

AlphaMissense predicts likely benign (score 0.0804) — an in-silico prediction, not a clinical call.

TRIP12 p.Val85Phe

c.253G>T · VCV3973864

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0804 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0804	likely benign
REVEL	0.186	benign-leaning
SaProt	LLR -8.49	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 6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 21 kb · p 0.78 · regional, not allelic
Overall
CADD	22.8	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V43F vs ClinVar V85F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0174% African / African-American · 13/74,832 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00814%

Overall 0.000868% 14/1,613,488 alleles · ultra-rare exomes 4/1,461,356 · genomes 10/152,132 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0174%	5,756
Remaining individualsnot grpmax-eligible	0.0016%	62,452

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: TRIP12
Protein: p.Val85Phe
Coding: c.253G>T
MANE Select: NM_001348323
Type: single nucleotide variant
Location: chr2:229859546 (GRCh38)
Gene constraint: LOEUF 0.145 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.06 · 5 PDB
Residue 43 UniProt numbering: the 'disordered' region

Full TRIP12 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

TRIP12 c.4215+4A>G Uncertain significance ★★ same condition
TRIP12 p.Ala1042Val Uncertain significance ★★ ⚠ same condition
TRIP12 p.Ala1766Thr Uncertain significance ★★ ⚠ same condition
TRIP12 p.Arg1666His Uncertain significance ★★ ⚠ same condition
TRIP12 p.Arg1803Trp Uncertain significance ★★ same condition
TRIP12 p.Arg275Leu Uncertain significance ★★ ⚠ same condition
TRIP12 p.Arg33Gly Uncertain significance ★★ ⚠ same condition
TRIP12 p.Asn1536Tyr 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/trip12-p-val85phe (accessed [today's date]).

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