Is TRPV6 p.Val431Met (c.1291G>A) pathogenic?

TRPV6 p.Val431Met (c.1291G>A) is classified Uncertain significance in TRPV6 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-19). AlphaMissense: likely benign (0.1366); Ultra-rare (popmax 0.011%, sas).

How common is TRPV6 p.Val431Met (c.1291G>A) in the general population?

TRPV6 p.Val431Met (c.1291G>A) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about TRPV6 p.Val431Met (c.1291G>A)?

AlphaMissense predicts likely benign (score 0.1366) — an in-silico prediction, not a clinical call.

TRPV6 p.Val431Met

c.1291G>A · VCV3609668

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1366 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1366	likely benign
REVEL	0.266	benign-leaning
SaProt	LLR -7.39	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 0.25	GERP 0.9, phastCons 0.013
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0025 · regional, not allelic
Overall
CADD	20.4	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 0.011% South Asian · 10/91,078 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00161% 26/1,614,170 alleles · ultra-rare exomes 26/1,461,892 · genomes 0/152,278 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,108
Remaining individualsnot grpmax-eligible	0.0048%	20,836
European (non-Finnish)	0.0011%	90,772

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: TRPV6
Protein: p.Val431Met
Coding: c.1291G>A
MANE Select: NM_018646
Type: single nucleotide variant
Location: chr7:142875116 (GRCh38)
Gene constraint: LOEUF 0.638 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.76 · 25 PDB
Residue 431: an α-helix

Full TRPV6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRPV6 p.Gly451Glu Pathogenic/Likely pathogenic ★★ same type
TRPV6 p.Ala122Val Uncertain significance ★★ ⚠ same type
TRPV6 p.Arg220Trp Uncertain significance ★★ ⚠ same type
TRPV6 p.Arg230Gln Uncertain significance ★★ ⚠ same type
TRPV6 p.Arg342Trp Uncertain significance ★★ ⚠ same type
TRPV6 p.Arg454Cys Uncertain significance ★★ ⚠ same type
TRPV6 p.Arg646Gln Uncertain significance ★★ ⚠ same type
TRPV6 p.Arg646Trp 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/trpv6-p-val431met (accessed [today's date]).

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