Is CMA1 p.Leu76Pro (c.227T>C) pathogenic?

CMA1 p.Leu76Pro (c.227T>C) is classified Uncertain significance in CMA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-30). AlphaMissense: likely pathogenic (0.917); Very rare (popmax 0.00667%, amr).

How common is CMA1 p.Leu76Pro (c.227T>C) in the general population?

CMA1 p.Leu76Pro (c.227T>C) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about CMA1 p.Leu76Pro (c.227T>C)?

AlphaMissense predicts likely pathogenic (score 0.917) — an in-silico prediction, not a clinical call.

CMA1 p.Leu76Pro

c.227T>C · VCV3494084

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.917 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.917	likely pathogenic · top 8% in CMA1
REVEL	0.853	moderately pathogenic-leaning
SaProt	LLR -15.71	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 1.39	unconstrained · MANE · 2,716 bp · p 1.1e-11 · regional, not allelic
Overall
CADD	28.5	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

Grpmax group 0.00667% Admixed American · 4/59,976 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000992% 16/1,613,266 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,994
South Asian	0.00329%	30,355
European (non-Finnish)	0.000763%	131,072

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.Leu76Pro
Coding: c.227T>C
MANE Select: NM_001836
Type: single nucleotide variant
Location: chr14:24506587 (GRCh38)
Gene constraint: LOEUF 1.578 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.55 · 42 PDB
Residue 76: 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-leu76pro (accessed [today's date]).

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