Is CALHM3 p.Leu50Pro (c.149T>C) pathogenic?

CALHM3 p.Leu50Pro (c.149T>C) is classified Uncertain significance in CALHM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-06). AlphaMissense: likely benign (0.1249); Absent from gnomAD v4.1.

How common is CALHM3 p.Leu50Pro (c.149T>C) in the general population?

CALHM3 p.Leu50Pro (c.149T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CALHM3 p.Leu50Pro (c.149T>C)?

AlphaMissense predicts likely benign (score 0.1249) — an in-silico prediction, not a clinical call.

CALHM3 p.Leu50Pro

c.149T>C · rs2540776793 · VCV2533701

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1249 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1249	likely benign
REVEL	0.238	benign-leaning
SaProt	LLR -7.52	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 6	GERP 0.031, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 5,816 bp · p 0.12 · regional, not allelic
Overall
CADD	22.4	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: CALHM3
Protein: p.Leu50Pro
Coding: c.149T>C
MANE Select: NM_001129742
dbSNP: rs2540776793
Type: single nucleotide variant
Location: chr10:103478884 (GRCh38)
Gene constraint: LOEUF 1.099 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.99
Residue 50: a disulfide bond

Full CALHM3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CALHM3 p.Ala106Val Uncertain significance ★ ⚠ same type
CALHM3 p.Ala108Val Uncertain significance ★ ⚠ same type
CALHM3 p.Ala109Thr Uncertain significance ★ ⚠ same type
CALHM3 p.Ala168Thr Uncertain significance ★ ⚠ same type
CALHM3 p.Ala235Val Uncertain significance ★ ⚠ same type
CALHM3 p.Ala248Val Uncertain significance ★ ⚠ same type
CALHM3 p.Ala256Thr Uncertain significance ★ ⚠ same type
CALHM3 p.Ala85Thr 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/calhm3-p-leu50pro (accessed [today's date]).

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