Is CALHM6 p.Trp113Arg (c.337T>C) pathogenic?

CALHM6 p.Trp113Arg (c.337T>C) is classified Uncertain significance in CALHM6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-09). AlphaMissense: likely pathogenic (0.9896); Very rare (popmax 0.00366%, amr).

How common is CALHM6 p.Trp113Arg (c.337T>C) in the general population?

CALHM6 p.Trp113Arg (c.337T>C) is very rare (popmax 0.00366%, amr) (gnomAD).

What do computational predictors say about CALHM6 p.Trp113Arg (c.337T>C)?

AlphaMissense predicts likely pathogenic (score 0.9896) — an in-silico prediction, not a clinical call.

CALHM6 p.Trp113Arg

c.337T>C · VCV3262979

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9896 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00366%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9896	likely pathogenic · top 1% in CALHM6
REVEL	0.544	indeterminate
SaProt	LLR -13.33	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.58, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 1,772 bp · p 0.53 · regional, not allelic
Overall
CADD	29.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00366% Admixed American · 1/27,334 alleles

Overall 0.000658% 1/152,070 alleles · very rare

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: CALHM6
Protein: p.Trp113Arg
Coding: c.337T>C
MANE Select: NM_001010919
Type: single nucleotide variant
Location: chr6:116462266 (GRCh38)
Gene constraint: LOEUF 1.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.83 · 2 PDB
Residue 113: a disulfide bond

Full CALHM6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CALHM6 p.Ala233Val Uncertain significance ★ ⚠ same type
CALHM6 p.Ala36Asp Uncertain significance ★ ⚠ same type
CALHM6 p.Ala62Ser Uncertain significance ★ ⚠ same type
CALHM6 p.Arg144Ser Uncertain significance ★ ⚠ same type
CALHM6 p.Arg73Gly Uncertain significance ★ ⚠ same type
CALHM6 p.Asn143Lys Uncertain significance ★ ⚠ same type
CALHM6 p.Asn236Ser Uncertain significance ★ ⚠ same type
CALHM6 p.Asn267Ser 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/calhm6-p-trp113arg (accessed [today's date]).

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