Is CALHM1 p.Arg89Trp (c.265C>T) pathogenic?

CALHM1 p.Arg89Trp (c.265C>T) is classified Uncertain significance in CALHM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-10). AlphaMissense: likely pathogenic (0.8824); Very rare (popmax 0.0028%, nfe).

How common is CALHM1 p.Arg89Trp (c.265C>T) in the general population?

CALHM1 p.Arg89Trp (c.265C>T) is very rare (popmax 0.0028%, nfe) (gnomAD).

What do computational predictors say about CALHM1 p.Arg89Trp (c.265C>T)?

AlphaMissense predicts likely pathogenic (score 0.8824) — an in-silico prediction, not a clinical call.

CALHM1 p.Arg89Trp

c.265C>T · VCV3484384

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8824 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8824	likely pathogenic
REVEL	0.208	benign-leaning
SaProt	LLR -5.34	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 0.12, phastCons 0.99
Regional constraint	o/e 0.92	unconstrained · MANE · 3,486 bp · p 0.085 · regional, not allelic
Overall
CADD	23.1	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 0.0028% European (non-Finnish) · 33/1,179,900 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00176%

Overall 0.00211% 34/1,612,860 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0028%	35,755
African / African-American	0.00133%	74,924

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.Arg89Trp
Coding: c.265C>T
MANE Select: NM_001001412
Type: single nucleotide variant
Location: chr10:103458487 (GRCh38)
Gene constraint: LOEUF 1.293 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.25 · 4 PDB
Residue 89: a disulfide bond

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

Similar variants

CALHM1 p.Arg89Gln Uncertain significance ★ ⚠ same residue
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

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-arg89trp (accessed [today's date]).

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