Is TREH p.Val431Met (c.1291G>A) pathogenic?

TREH p.Val431Met (c.1291G>A) is classified Uncertain significance in TREH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-05). AlphaMissense: likely benign (0.125); Ultra-rare (popmax 0.0161%, eas).

How common is TREH p.Val431Met (c.1291G>A) in the general population?

TREH p.Val431Met (c.1291G>A) is ultra-rare (popmax 0.0161%, eas) (gnomAD).

What do computational predictors say about TREH p.Val431Met (c.1291G>A)?

AlphaMissense predicts likely benign (score 0.125) — an in-silico prediction, not a clinical call.

TREH p.Val431Met

c.1291G>A · rs782261584 · VCV3182081

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.125 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0161%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.125	likely benign
REVEL	0.066	moderately benign-leaning
SaProt	LLR -7.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.5	GERP -3.4
Regional constraint	o/e 1.00	unconstrained · MANE · 21 kb · p 0.92 · regional, not allelic
Overall
CADD	3.864	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 0.0161% East Asian · 7/43,420 alleles

Filtering AF 0.00747% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00528%

Overall 0.00133% 21/1,583,562 alleles · ultra-rare exomes 19/1,431,350 · genomes 2/152,212 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0161%	6,203
Remaining individualsnot grpmax-eligible	0.00163%	61,420
European (non-Finnish)	0.00112%	89,569

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: TREH
Protein: p.Val431Met
Coding: c.1291G>A
MANE Select: NM_007180
dbSNP: rs782261584
Type: single nucleotide variant
Location: chr11:118659776 (GRCh38)
Gene constraint: LOEUF 1.19 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.80

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

Similar variants

TREH p.Gln87Lys Uncertain significance ★★ ⚠ same type
TREH p.Lys140Arg Likely benign ★★ same type
TREH p.Tyr449His Likely benign ★★ same type
TREH p.Ala307Val Uncertain significance ★ ⚠ same type
TREH p.Ala356Thr Uncertain significance ★ ⚠ same type
TREH p.Ala373Asp Uncertain significance ★ same type
TREH p.Ala469Asp Uncertain significance ★ ⚠ same type
TREH p.Arg125Cys 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/treh-p-val431met (accessed [today's date]).

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