Is CMA1 p.Ile41Ser (c.122T>G) pathogenic?

CMA1 p.Ile41Ser (c.122T>G) is classified Uncertain significance in CMA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely pathogenic (0.5929); Absent from gnomAD v4.1.

How common is CMA1 p.Ile41Ser (c.122T>G) in the general population?

CMA1 p.Ile41Ser (c.122T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CMA1 p.Ile41Ser (c.122T>G)?

AlphaMissense predicts likely pathogenic (score 0.5929) — an in-silico prediction, not a clinical call.

CMA1 p.Ile41Ser

c.122T>G · VCV4230424

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5929 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5929	likely pathogenic
REVEL	0.599	indeterminate
SaProt	LLR -7.76	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 2.2, phastCons 0.002
Regional constraint	o/e 1.39	unconstrained · MANE · 2,716 bp · p 1.1e-11 · regional, not allelic
Overall
CADD	21.7	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

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.Ile41Ser
Coding: c.122T>G
MANE Select: NM_001836
Type: single nucleotide variant
Location: chr14:24507443 (GRCh38)
Gene constraint: LOEUF 1.578 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.55 · 42 PDB
Residue 41: a β-strand; 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.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-ile41ser (accessed [today's date]).

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