Is CALHM6 p.Leu49Pro (c.146T>C) pathogenic?

CALHM6 p.Leu49Pro (c.146T>C) is classified Uncertain significance in CALHM6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-13). AlphaMissense: likely pathogenic (0.5703); Absent from gnomAD v4.1.

How common is CALHM6 p.Leu49Pro (c.146T>C) in the general population?

CALHM6 p.Leu49Pro (c.146T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CALHM6 p.Leu49Pro (c.146T>C)?

AlphaMissense predicts likely pathogenic (score 0.5703) — an in-silico prediction, not a clinical call.

CALHM6 p.Leu49Pro

c.146T>C · rs938014565 · VCV2623343

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5703 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,547,562)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5703	likely pathogenic
REVEL	0.236	benign-leaning
SaProt	LLR -12.17	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -0.77, phastCons 0.22
Regional constraint	o/e 1.03	unconstrained · MANE · 1,772 bp · p 0.53 · regional, not allelic
Overall
CADD	22.6	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

No allele count reported in gnomAD v4.1 (AN 1,547,562). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CALHM6
Protein: p.Leu49Pro
Coding: c.146T>C
MANE Select: NM_001010919
dbSNP: rs938014565
Type: single nucleotide variant
Location: chr6:116462075 (GRCh38)
Gene constraint: LOEUF 1.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.83 · 2 PDB
Residue 49: a disulfide bond

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

Similar variants

CALHM6 p.Leu49Val Uncertain significance ★ ⚠ same residue
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

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-leu49pro (accessed [today's date]).

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