Is CALHM3 p.Ala248Val (c.743C>T) pathogenic?

CALHM3 p.Ala248Val (c.743C>T) is classified Uncertain significance in CALHM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-29). AlphaMissense: likely benign (0.1453); Very rare (popmax 0.00684%, afr).

How common is CALHM3 p.Ala248Val (c.743C>T) in the general population?

CALHM3 p.Ala248Val (c.743C>T) is very rare (popmax 0.00684%, afr) (gnomAD).

What do computational predictors say about CALHM3 p.Ala248Val (c.743C>T)?

AlphaMissense predicts likely benign (score 0.1453) — an in-silico prediction, not a clinical call.

CALHM3 p.Ala248Val

c.743C>T · rs919841470 · VCV2280831

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1453 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00684%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1453	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -7.56	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 3	GERP -0.16, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 5,816 bp · p 0.12 · regional, not allelic
Overall
CADD	23.2	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 0.00684% African / African-American · 5/73,064 alleles

Filtering AF 0.00377% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00338%

Overall 0.00413% 64/1,550,828 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00684%	14,613
Remaining individualsnot grpmax-eligible	0.00666%	15,020
European (non-Finnish)	0.0048%	20,853

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.Ala248Val
Coding: c.743C>T
MANE Select: NM_001129742
dbSNP: rs919841470
Type: single nucleotide variant
Location: chr10:103473505 (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.Ala256Thr Uncertain significance ★ ⚠ same type
CALHM3 p.Ala85Thr Uncertain significance ★ ⚠ same type
CALHM3 p.Arg169Gln 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-ala248val (accessed [today's date]).

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