Is CALHM1 p.Arg97His (c.290G>A) pathogenic?

CALHM1 p.Arg97His (c.290G>A) is classified Uncertain significance in CALHM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-06). AlphaMissense: likely benign (0.2978); Very rare (popmax 0.00834%, amr).

How common is CALHM1 p.Arg97His (c.290G>A) in the general population?

CALHM1 p.Arg97His (c.290G>A) is very rare (popmax 0.00834%, amr) (gnomAD).

What do computational predictors say about CALHM1 p.Arg97His (c.290G>A)?

AlphaMissense predicts likely benign (score 0.2978) — an in-silico prediction, not a clinical call.

CALHM1 p.Arg97His

c.290G>A · rs770402855 · VCV2480698

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2978 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2978	likely benign
REVEL	0.307	indeterminate
SaProt	LLR -9.40	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 3,486 bp · p 0.085 · regional, not allelic
Overall
CADD	27.2	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 0.00834% Admixed American · 5/59,976 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00294%

Overall 0.00397% 64/1,612,954 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00834%	11,995
Remaining individualsnot grpmax-eligible	0.00801%	12,492
European (non-Finnish)	0.00424%	23,597
African / African-American	0.00267%	37,472
South Asian	0.0022%	45,524

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: CALHM1
Protein: p.Arg97His
Coding: c.290G>A
MANE Select: NM_001001412
dbSNP: rs770402855
Type: single nucleotide variant
Location: chr10:103458462 (GRCh38)
Gene constraint: LOEUF 1.293 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.25 · 4 PDB
Residue 97: a disulfide bond; an α-helix

Full CALHM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CALHM1 p.Ala153Thr Benign ★★ same type
CALHM1 p.Arg154His Likely pathogenic ★ ⚠ same type
CALHM1 p.Ala107Thr Uncertain significance ★ ⚠ same type
CALHM1 p.Ala110Val Uncertain significance ★ ⚠ same type
CALHM1 p.Ala137Thr Uncertain significance ★ ⚠ same type
CALHM1 p.Ala172Pro Uncertain significance ★ ⚠ same type
CALHM1 p.Ala186Val Uncertain significance ★ ⚠ same type
CALHM1 p.Ala212Ser 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/calhm1-p-arg97his (accessed [today's date]).

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