Is CHRM4 p.Val175Ala (c.524T>C) pathogenic?

CHRM4 p.Val175Ala (c.524T>C) is classified Uncertain significance in CHRM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-17). AlphaMissense: likely benign (0.1613); Very rare (popmax 0.00212%, nfe).

How common is CHRM4 p.Val175Ala (c.524T>C) in the general population?

CHRM4 p.Val175Ala (c.524T>C) is very rare (popmax 0.00212%, nfe) (gnomAD).

What do computational predictors say about CHRM4 p.Val175Ala (c.524T>C)?

AlphaMissense predicts likely benign (score 0.1613) — an in-silico prediction, not a clinical call.

CHRM4 p.Val175Ala

c.524T>C · rs1215759352 · VCV2612271

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1613 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1613	likely benign
REVEL	0.141	moderately benign-leaning
SaProt	LLR -8.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.91, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 282 bp · p 9.6e-13 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00212% European (non-Finnish) · 25/1,179,804 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00155% 25/1,613,192 alleles · very rare exomes 24/1,460,990 · genomes 1/152,202 · joint denominator

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: CHRM4
Protein: p.Val175Ala
Coding: c.524T>C
MANE Select: NM_000741
dbSNP: rs1215759352
Type: single nucleotide variant
Location: chr11:46386034 (GRCh38)
Gene constraint: LOEUF 0.398 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 39 PDB
Residue 175: a β-strand

Full CHRM4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHRM4 p.Ala263Thr Uncertain significance ★ ⚠ same type
CHRM4 p.Ala325Thr Uncertain significance ★ ⚠ same type
CHRM4 p.Ala356Thr Uncertain significance ★ ⚠ same type
CHRM4 p.Arg17His Uncertain significance ★ ⚠ same type
CHRM4 p.Arg264Gly Uncertain significance ★ ⚠ same type
CHRM4 p.Arg268Cys Uncertain significance ★ ⚠ same type
CHRM4 p.Arg285Cys Uncertain significance ★ ⚠ same type
CHRM4 p.Arg308His 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/chrm4-p-val175ala (accessed [today's date]).

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