Is CMA1 p.Arg221Trp (c.661C>T) pathogenic?

CMA1 p.Arg221Trp (c.661C>T) is classified Uncertain significance in CMA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-19). AlphaMissense: likely benign (0.2279); Ultra-rare (popmax 0.055%, amr).

How common is CMA1 p.Arg221Trp (c.661C>T) in the general population?

CMA1 p.Arg221Trp (c.661C>T) is ultra-rare (popmax 0.055%, amr) (gnomAD).

What do computational predictors say about CMA1 p.Arg221Trp (c.661C>T)?

AlphaMissense predicts likely benign (score 0.2279) — an in-silico prediction, not a clinical call.

CMA1 p.Arg221Trp

c.661C>T · VCV3494083

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2279 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.055%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2279	likely benign
REVEL	0.289	benign-leaning
SaProt	LLR -11.07	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.6	GERP -4.5
Regional constraint	o/e 1.39	unconstrained · MANE · 2,716 bp · p 1.1e-11 · regional, not allelic
Overall
CADD	17.1	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 0.055% Admixed American · 33/60,014 alleles

Filtering AF 0.0402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0351%

Overall 0.00308% 45/1,461,740 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.055%	1,819
Remaining individualsnot grpmax-eligible	0.0016%	62,484
South Asian	0.0011%	91,064
European (non-Finnish)	0.000847%	118,000

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: CMA1
Protein: p.Arg221Trp
Coding: c.661C>T
MANE Select: NM_001836
Type: single nucleotide variant
Location: chr14:24505599 (GRCh38)
Gene constraint: LOEUF 1.578 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.55 · 42 PDB
Residue 221: the peptidase s1 domain

Full CMA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CMA1 p.Gly46Arg Likely benign ★★ same type
CMA1 p.Ala19Thr Uncertain significance ★ ⚠ same type
CMA1 p.Ala246Thr Uncertain significance ★ ⚠ same type
CMA1 p.Arg145Gln Uncertain significance ★ ⚠ same type
CMA1 p.Arg151Gly Uncertain significance ★ same type
CMA1 p.Asn45Lys Uncertain significance ★ ⚠ same type
CMA1 p.Asn59Lys Uncertain significance ★ ⚠ same type
CMA1 p.Asp86Tyr 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/cma1-p-arg221trp (accessed [today's date]).

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