Is CALHM2 p.Leu198Pro (c.593T>C) pathogenic?

CALHM2 p.Leu198Pro (c.593T>C) is classified Uncertain significance in CALHM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-17). AlphaMissense: ambiguous (0.4606); Ultra-rare (popmax 0.0117%, amr).

How common is CALHM2 p.Leu198Pro (c.593T>C) in the general population?

CALHM2 p.Leu198Pro (c.593T>C) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about CALHM2 p.Leu198Pro (c.593T>C)?

AlphaMissense predicts ambiguous (score 0.4606) — an in-silico prediction, not a clinical call.

CALHM2 p.Leu198Pro

c.593T>C · rs748008272 · VCV2222275

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4606 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4606	ambiguous
REVEL	0.211	benign-leaning
SaProt	LLR -11.34	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 2,786 bp · p 0.24 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/59,600 alleles

Filtering AF 0.00547% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00383%

Overall 0.000684% 11/1,607,130 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,514
Remaining individualsnot grpmax-eligible	0.00322%	31,077
African / African-American	0.00134%	74,852
European (non-Finnish)	8.51e-05%	1,175,386

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: CALHM2
Protein: p.Leu198Pro
Coding: c.593T>C
MANE Select: NM_015916
dbSNP: rs748008272
Type: single nucleotide variant
Location: chr10:103447531 (GRCh38)
Gene constraint: LOEUF 1.212 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.52 · 12 PDB
Residue 198: an α-helix

Full CALHM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CALHM2 p.Ala110Val Uncertain significance ★ ⚠ same type
CALHM2 p.Ala243Thr Uncertain significance ★ ⚠ same type
CALHM2 p.Ala311Val Uncertain significance ★ ⚠ same type
CALHM2 p.Ala59Val Uncertain significance ★ ⚠ same type
CALHM2 p.Ala97Thr Uncertain significance ★ ⚠ same type
CALHM2 p.Arg109Cys Uncertain significance ★ ⚠ same type
CALHM2 p.Arg109His Uncertain significance ★ ⚠ same type
CALHM2 p.Arg10His 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/calhm2-p-leu198pro (accessed [today's date]).

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