Is CALHM3 p.Val172Met (c.514G>A) pathogenic?

CALHM3 p.Val172Met (c.514G>A) is classified Uncertain significance in CALHM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-08). AlphaMissense: ambiguous (0.4213); Ultra-rare (popmax 0.0171%, eas).

How common is CALHM3 p.Val172Met (c.514G>A) in the general population?

CALHM3 p.Val172Met (c.514G>A) is ultra-rare (popmax 0.0171%, eas) (gnomAD).

What do computational predictors say about CALHM3 p.Val172Met (c.514G>A)?

AlphaMissense predicts ambiguous (score 0.4213) — an in-silico prediction, not a clinical call.

CALHM3 p.Val172Met

c.514G>A · VCV3826939

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4213 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0171%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4213	ambiguous
REVEL	0.232	benign-leaning
SaProt	LLR -9.83	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.4, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 5,816 bp · p 0.12 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0171% East Asian · 7/40,934 alleles

Filtering AF 0.00798% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00564%

Overall 0.00148% 23/1,551,462 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0171%	5,848
African / African-American	0.0123%	8,118
South Asian	0.00238%	42,034
Remaining individualsnot grpmax-eligible	0.00166%	60,096
European (non-Finnish)	0.000349%	286,751

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: CALHM3
Protein: p.Val172Met
Coding: c.514G>A
MANE Select: NM_001129742
Type: single nucleotide variant
Location: chr10:103476323 (GRCh38)
Gene constraint: LOEUF 1.099 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.99

Full CALHM3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CALHM3 p.Ala106Val Uncertain significance ★ ⚠ same type
CALHM3 p.Ala108Val Uncertain significance ★ ⚠ same type
CALHM3 p.Ala109Thr Uncertain significance ★ ⚠ same type
CALHM3 p.Ala168Thr Uncertain significance ★ ⚠ same type
CALHM3 p.Ala235Val Uncertain significance ★ ⚠ same type
CALHM3 p.Ala248Val Uncertain significance ★ ⚠ same type
CALHM3 p.Ala256Thr Uncertain significance ★ ⚠ same type
CALHM3 p.Ala85Thr 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/calhm3-p-val172met (accessed [today's date]).

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