Is CHRM5 p.Leu321Phe (c.961C>T) pathogenic?

CHRM5 p.Leu321Phe (c.961C>T) is classified Likely benign in CHRM5 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-25). AlphaMissense: likely benign (0.0526); Ultra-rare (popmax 0.0417%, sas).

How common is CHRM5 p.Leu321Phe (c.961C>T) in the general population?

CHRM5 p.Leu321Phe (c.961C>T) is ultra-rare (popmax 0.0417%, sas) (gnomAD).

What do computational predictors say about CHRM5 p.Leu321Phe (c.961C>T)?

AlphaMissense predicts likely benign (score 0.0526) — an in-silico prediction, not a clinical call.

CHRM5 p.Leu321Phe

c.961C>T · VCV4839689

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0526 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0417%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0526	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -7.40	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 2.7	GERP 0.75, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 1,595 bp · p 9.6e-08 · regional, not allelic
Overall
CADD	9.324	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 0.0417% South Asian · 38/91,084 alleles

Filtering AF 0.0312% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0275%

Overall 0.00248% 40/1,614,056 alleles · ultra-rare exomes 39/1,461,894 · genomes 1/152,162 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0417%	2,397
Remaining individualsnot grpmax-eligible	0.0032%	31,244

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: CHRM5
Protein: p.Leu321Phe
Coding: c.961C>T
MANE Select: NM_012125
Type: single nucleotide variant
Location: chr15:34063678 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI 0.09 (gnomAD)
Structure: AlphaFold pLDDT 69.14 · 2 PDB

Full CHRM5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHRM5 p.Glu412Lys Benign ★★ same type
CHRM5 p.Pro191= Benign ★★ same type
CHRM5 p.Ala165Thr Uncertain significance ★ ⚠ same type
CHRM5 p.Ala269Pro Uncertain significance ★ ⚠ same type
CHRM5 p.Ala339Val Uncertain significance ★ ⚠ same type
CHRM5 p.Ala366Thr Uncertain significance ★ ⚠ same type
CHRM5 p.Ala441Val Uncertain significance ★ ⚠ same type
CHRM5 p.Ala9Gly 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/chrm5-p-leu321phe (accessed [today's date]).

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