Is CMA1 p.Cys209Ser (c.626G>C) pathogenic?

CMA1 p.Cys209Ser (c.626G>C) is classified Uncertain significance in CMA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-31). AlphaMissense: likely pathogenic (0.9723); Absent from gnomAD v4.1.

How common is CMA1 p.Cys209Ser (c.626G>C) in the general population?

CMA1 p.Cys209Ser (c.626G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CMA1 p.Cys209Ser (c.626G>C)?

AlphaMissense predicts likely pathogenic (score 0.9723) — an in-silico prediction, not a clinical call.

CMA1 p.Cys209Ser

c.626G>C · rs2502584354 · VCV2553416

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9723 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9723	likely pathogenic · top 1% in CMA1
REVEL	0.513	indeterminate
SaProt	LLR -11.73	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 2.2, phastCons 1
Regional constraint	o/e 1.39	unconstrained · MANE · 2,716 bp · p 1.1e-11 · regional, not allelic
Overall
CADD	24.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CMA1
Protein: p.Cys209Ser
Coding: c.626G>C
MANE Select: NM_001836
dbSNP: rs2502584354
Type: single nucleotide variant
Location: chr14:24505634 (GRCh38)
Gene constraint: LOEUF 1.578 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.55 · 42 PDB
Residue 209: a disulfide bond; the peptidase s1 domain; a β-strand

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.Arg221Trp Uncertain significance ★ ⚠ same type
CMA1 p.Asn45Lys Uncertain significance ★ ⚠ same type
CMA1 p.Asn59Lys 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-cys209ser (accessed [today's date]).

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