Is CALHM5 p.Leu289Pro (c.866T>C) pathogenic?

CALHM5 p.Leu289Pro (c.866T>C) is classified Uncertain significance in CALHM5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: likely benign (0.1); Absent from gnomAD v4.1.

How common is CALHM5 p.Leu289Pro (c.866T>C) in the general population?

CALHM5 p.Leu289Pro (c.866T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CALHM5 p.Leu289Pro (c.866T>C)?

AlphaMissense predicts likely benign (score 0.1) — an in-silico prediction, not a clinical call.

CALHM5 p.Leu289Pro

c.866T>C · rs2482450916 · VCV3136730

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1	likely benign
REVEL	0.142	moderately benign-leaning
SaProt	LLR -4.56	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 2.8	GERP 0.64, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 4,289 bp · p 0.81 · regional, not allelic
Overall
CADD	17.65	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: CALHM5
Protein: p.Leu289Pro
Coding: c.866T>C
MANE Select: NM_153711
dbSNP: rs2482450916
Type: single nucleotide variant
Location: chr6:116515925 (GRCh38)
Gene constraint: LOEUF 1.13 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.42 · 3 PDB

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-leu289pro (accessed [today's date]).

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