Is CALHM6 p.Leu61Val (c.181C>G) pathogenic?

CALHM6 p.Leu61Val (c.181C>G) is classified Uncertain significance in CALHM6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-19). AlphaMissense: likely benign (0.1153); Absent from gnomAD v4.1.

How common is CALHM6 p.Leu61Val (c.181C>G) in the general population?

CALHM6 p.Leu61Val (c.181C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CALHM6 p.Leu61Val (c.181C>G)?

AlphaMissense predicts likely benign (score 0.1153) — an in-silico prediction, not a clinical call.

CALHM6 p.Leu61Val

c.181C>G · VCV4218347

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1153 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1153	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -6.72	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 0.13	GERP 0.99
Regional constraint	o/e 1.03	unconstrained · MANE · 1,772 bp · p 0.53 · regional, not allelic
Overall
CADD	21.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CALHM6
Protein: p.Leu61Val
Coding: c.181C>G
MANE Select: NM_001010919
Type: single nucleotide variant
Location: chr6:116462110 (GRCh38)
Gene constraint: LOEUF 1.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.83 · 2 PDB
Residue 61: 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-leu61val (accessed [today's date]).

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