Is CALHM4 p.Ser240Phe (c.719C>T) pathogenic?

CALHM4 p.Ser240Phe (c.719C>T) is classified Uncertain significance in CALHM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-04). AlphaMissense: likely pathogenic (0.7079); Very rare (popmax 0.0039%, nfe).

How common is CALHM4 p.Ser240Phe (c.719C>T) in the general population?

CALHM4 p.Ser240Phe (c.719C>T) is very rare (popmax 0.0039%, nfe) (gnomAD).

What do computational predictors say about CALHM4 p.Ser240Phe (c.719C>T)?

AlphaMissense predicts likely pathogenic (score 0.7079) — an in-silico prediction, not a clinical call.

CALHM4 p.Ser240Phe

c.719C>T · VCV3994823

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7079 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0039%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7079	likely pathogenic · top 7% in CALHM4
REVEL	0.257	benign-leaning
SaProt	LLR -7.70	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 4.8	GERP 0.95, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 4,414 bp · p 0.11 · regional, not allelic
Overall
CADD	25.3	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 0.0039% European (non-Finnish) · 46/1,180,034 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00267%

Overall 0.00291% 47/1,614,012 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0039%	25,653
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: CALHM4
Protein: p.Ser240Phe
Coding: c.719C>T
MANE Select: NM_001366078
Type: single nucleotide variant
Location: chr6:116557985 (GRCh38)
Gene constraint: LOEUF 1.551 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.63 · 7 PDB
Residue 240: an α-helix

Full CALHM4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CALHM4 p.Ser240Pro Uncertain significance ★ ⚠ same residue
CALHM4 p.Ala199Thr Uncertain significance ★ ⚠ same type
CALHM4 p.Arg241Trp Uncertain significance ★ ⚠ same type
CALHM4 p.Arg247His Uncertain significance ★ ⚠ same type
CALHM4 p.Arg265His Uncertain significance ★ ⚠ same type
CALHM4 p.Arg306Gly Uncertain significance ★ ⚠ same type
CALHM4 p.Asp260Val Uncertain significance ★ ⚠ same type
CALHM4 p.Cys204Arg 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/calhm4-p-ser240phe (accessed [today's date]).

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