Is CALHM4 p.Lys262Arg (c.785A>G) pathogenic?

CALHM4 p.Lys262Arg (c.785A>G) is classified Uncertain significance in CALHM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-01). AlphaMissense: likely benign (0.0718); Rare (popmax 0.123%, eas).

How common is CALHM4 p.Lys262Arg (c.785A>G) in the general population?

CALHM4 p.Lys262Arg (c.785A>G) is rare (popmax 0.123%, eas) (gnomAD).

What do computational predictors say about CALHM4 p.Lys262Arg (c.785A>G)?

AlphaMissense predicts likely benign (score 0.0718) — an in-silico prediction, not a clinical call.

CALHM4 p.Lys262Arg

c.785A>G · rs193203831 · VCV3136713

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0718 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.123%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0718	likely benign
REVEL	0.008	strongly benign-leaning
SaProt	LLR -6.74	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 -0.28	GERP -3.7
Regional constraint	o/e 0.92	unconstrained · MANE · 4,414 bp · p 0.11 · regional, not allelic
Overall
CADD	2.409	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 0.123% East Asian · 55/44,874 alleles

Filtering AF 0.0967% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0873%

Overall 0.00434% 70/1,614,182 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.123%	816
Amishnot grpmax-eligible	0.11%	912
African / African-American	0.0133%	7,505
Remaining individualsnot grpmax-eligible	0.0048%	20,837
European (non-Finnish)	8.47e-05%	1,180,022

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: CALHM4
Protein: p.Lys262Arg
Coding: c.785A>G
MANE Select: NM_001366078
dbSNP: rs193203831
Type: single nucleotide variant
Location: chr6:116558051 (GRCh38)
Gene constraint: LOEUF 1.551 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.63 · 7 PDB

Full CALHM4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CALHM4 p.Ala199Thr Uncertain significance ★ ⚠ same type
CALHM4 p.Arg241Trp Uncertain significance ★ ⚠ same type
CALHM4 p.Arg247His Uncertain significance ★ ⚠ same type
CALHM4 p.Arg265His Uncertain significance ★ ⚠ same type
CALHM4 p.Arg306Gly Uncertain significance ★ ⚠ same type
CALHM4 p.Asp260Val Uncertain significance ★ ⚠ same type
CALHM4 p.Cys204Arg Uncertain significance ★ ⚠ same type
CALHM4 p.Cys209Arg 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/calhm4-p-lys262arg (accessed [today's date]).

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