Is CALHM2 p.Ser184Phe (c.551C>T) pathogenic?

CALHM2 p.Ser184Phe (c.551C>T) is classified Uncertain significance in CALHM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). AlphaMissense: likely pathogenic (0.9948); Very rare (popmax 0.00167%, amr).

How common is CALHM2 p.Ser184Phe (c.551C>T) in the general population?

CALHM2 p.Ser184Phe (c.551C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CALHM2 p.Ser184Phe (c.551C>T)?

AlphaMissense predicts likely pathogenic (score 0.9948) — an in-silico prediction, not a clinical call.

CALHM2 p.Ser184Phe

c.551C>T · VCV4647792

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9948 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9948	likely pathogenic · top 1% in CALHM2
REVEL	0.866	moderately pathogenic-leaning
SaProt	LLR -15.05	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 2,786 bp · p 0.24 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00167% Admixed American · 1/60,022 alleles

Overall 0.000137% 2/1,460,024 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,022
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Ser184Phe
Coding: c.551C>T
MANE Select: NM_015916
Type: single nucleotide variant
Location: chr10:103449391 (GRCh38)
Gene constraint: LOEUF 1.212 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.52 · 12 PDB
Residue 184: 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-ser184phe (accessed [today's date]).

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