Is CALHM3 p.Ser339Pro (c.1015T>C) pathogenic?

CALHM3 p.Ser339Pro (c.1015T>C) is classified Uncertain significance in CALHM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). AlphaMissense: likely benign (0.0577); Ultra-rare (popmax 0.0102%, afr).

How common is CALHM3 p.Ser339Pro (c.1015T>C) in the general population?

CALHM3 p.Ser339Pro (c.1015T>C) is ultra-rare (popmax 0.0102%, afr) (gnomAD).

What do computational predictors say about CALHM3 p.Ser339Pro (c.1015T>C)?

AlphaMissense predicts likely benign (score 0.0577) — an in-silico prediction, not a clinical call.

CALHM3 p.Ser339Pro

c.1015T>C · VCV3484396

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0577 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0102%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0577	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -6.03	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 0.37	GERP -4.1, phastCons 0.001
Regional constraint	o/e 1.07	unconstrained · MANE · 5,816 bp · p 0.12 · regional, not allelic
Overall
CADD	7.738	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 0.0102% African / African-American · 7/68,806 alleles

Filtering AF 0.00472% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00331%

Overall 0.000937% 12/1,280,756 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0102%	9,829
Remaining individualsnot grpmax-eligible	0.00912%	10,969

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: CALHM3
Protein: p.Ser339Pro
Coding: c.1015T>C
MANE Select: NM_001129742
Type: single nucleotide variant
Location: chr10:103473233 (GRCh38)
Gene constraint: LOEUF 1.099 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.99

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-ser339pro (accessed [today's date]).

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