Is CALHM5 p.Leu63Pro (c.188T>C) pathogenic?

CALHM5 p.Leu63Pro (c.188T>C) is classified Uncertain significance in CALHM5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-02). AlphaMissense: likely pathogenic (0.8582); Very rare (popmax 0.00223%, eas).

How common is CALHM5 p.Leu63Pro (c.188T>C) in the general population?

CALHM5 p.Leu63Pro (c.188T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CALHM5 p.Leu63Pro (c.188T>C)?

AlphaMissense predicts likely pathogenic (score 0.8582) — an in-silico prediction, not a clinical call.

CALHM5 p.Leu63Pro

c.188T>C · rs1252286717 · VCV3136716

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8582 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8582	likely pathogenic · top 8% in CALHM5
REVEL	0.779	moderately pathogenic-leaning
SaProt	LLR -14.39	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 4,289 bp · p 0.81 · regional, not allelic
Overall
CADD	29.1	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 0.00223% East Asian · 1/44,878 alleles

Overall 6.84e-05% 1/1,461,814 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: CALHM5
Protein: p.Leu63Pro
Coding: c.188T>C
MANE Select: NM_153711
dbSNP: rs1252286717
Type: single nucleotide variant
Location: chr6:116511884 (GRCh38)
Gene constraint: LOEUF 1.13 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.42 · 3 PDB
Residue 63: a disulfide bond; an α-helix

Full CALHM5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CALHM5 p.Ala177Val Uncertain significance ★ ⚠ same type
CALHM5 p.Ala190Val Uncertain significance ★ ⚠ same type
CALHM5 p.Arg202Cys Uncertain significance ★ ⚠ same type
CALHM5 p.Arg202His Uncertain significance ★ ⚠ same type
CALHM5 p.Arg204Gln Uncertain significance ★ ⚠ same type
CALHM5 p.Arg32Ser Uncertain significance ★ ⚠ same type
CALHM5 p.Arg90Ser Uncertain significance ★ ⚠ same type
CALHM5 p.Asn121Ser 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/calhm5-p-leu63pro (accessed [today's date]).

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