Is CALHM2 p.Phe100Leu (c.298T>C) pathogenic?

CALHM2 p.Phe100Leu (c.298T>C) is classified Uncertain significance in CALHM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: likely pathogenic (0.7164); Very rare (popmax 0.00446%, eas).

How common is CALHM2 p.Phe100Leu (c.298T>C) in the general population?

CALHM2 p.Phe100Leu (c.298T>C) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CALHM2 p.Phe100Leu (c.298T>C)?

AlphaMissense predicts likely pathogenic (score 0.7164) — an in-silico prediction, not a clinical call.

CALHM2 p.Phe100Leu

c.298T>C · VCV4218324

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7164 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7164	likely pathogenic
REVEL	0.161	moderately benign-leaning
SaProt	LLR -5.07	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 2,786 bp · p 0.24 · regional, not allelic
Overall
CADD	22.3	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 0.00446% East Asian · 2/44,880 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000274% 4/1,461,582 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,440
European (non-Finnish)	0.000169%	590,009

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.Phe100Leu
Coding: c.298T>C
MANE Select: NM_015916
Type: single nucleotide variant
Location: chr10:103449644 (GRCh38)
Gene constraint: LOEUF 1.212 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.52 · 12 PDB
Residue 100: a disulfide bond; 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-phe100leu (accessed [today's date]).

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