Is CALHM5 p.Pro293Leu (c.878C>T) pathogenic?

CALHM5 p.Pro293Leu (c.878C>T) is classified Uncertain significance in CALHM5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-07). AlphaMissense: likely benign (0.0746); Ultra-rare (popmax 0.0267%, afr).

How common is CALHM5 p.Pro293Leu (c.878C>T) in the general population?

CALHM5 p.Pro293Leu (c.878C>T) is ultra-rare (popmax 0.0267%, afr) (gnomAD).

What do computational predictors say about CALHM5 p.Pro293Leu (c.878C>T)?

AlphaMissense predicts likely benign (score 0.0746) — an in-silico prediction, not a clinical call.

CALHM5 p.Pro293Leu

c.878C>T · VCV3484402

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0746 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0746	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -6.68	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 1.1	GERP 0.99
Regional constraint	o/e 0.99	unconstrained · MANE · 4,289 bp · p 0.81 · regional, not allelic
Overall
CADD	18.15	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

Grpmax group 0.0267% African / African-American · 20/74,984 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.0013% 21/1,613,018 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0267%	3,749
Remaining individualsnot grpmax-eligible	0.0016%	62,450

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.Pro293Leu
Coding: c.878C>T
MANE Select: NM_153711
Type: single nucleotide variant
Location: chr6:116515937 (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-pro293leu (accessed [today's date]).

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