Is CALHM2 p.Phe148Leu (c.444C>G) pathogenic?

CALHM2 p.Phe148Leu (c.444C>G) is classified Uncertain significance in CALHM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-04). AlphaMissense: likely pathogenic (0.7995); Very rare (popmax 8.47e-05%, nfe).

How common is CALHM2 p.Phe148Leu (c.444C>G) in the general population?

CALHM2 p.Phe148Leu (c.444C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CALHM2 p.Phe148Leu (c.444C>G)?

AlphaMissense predicts likely pathogenic (score 0.7995) — an in-silico prediction, not a clinical call.

CALHM2 p.Phe148Leu

c.444C>G · rs1187670674 · VCV2520578

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7995 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7995	likely pathogenic
REVEL	0.153	moderately benign-leaning
SaProt	LLR -5.21	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 3.3	GERP 2.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 2,786 bp · p 0.24 · regional, not allelic
Overall
CADD	16.91	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 8.47e-05% European (non-Finnish) · 1/1,180,024 alleles

Overall 0.000124% 2/1,613,388 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)grpmax	8.47e-05%	1,180,025

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe148Leu
Coding: c.444C>G
MANE Select: NM_015916
dbSNP: rs1187670674
Type: single nucleotide variant
Location: chr10:103449498 (GRCh38)
Gene constraint: LOEUF 1.212 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.52 · 12 PDB
Residue 148: the 'hemichannel docking' region; a disulfide bond

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-phe148leu (accessed [today's date]).

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