Is CMA1 p.Val217Ile (c.649G>A) pathogenic?

CMA1 p.Val217Ile (c.649G>A) is classified Uncertain significance in CMA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-28). AlphaMissense: likely benign (0.1688); Rare (popmax 0.169%, mid).

How common is CMA1 p.Val217Ile (c.649G>A) in the general population?

CMA1 p.Val217Ile (c.649G>A) is rare (popmax 0.169%, mid) (gnomAD).

What do computational predictors say about CMA1 p.Val217Ile (c.649G>A)?

AlphaMissense predicts likely benign (score 0.1688) — an in-silico prediction, not a clinical call.

CMA1 p.Val217Ile

c.649G>A · rs143164371 · VCV2351455

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1688 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.169%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1688	likely benign
REVEL	0.2	benign-leaning
SaProt	LLR -9.43	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 0.93	GERP 2.2, phastCons 0.3
Regional constraint	o/e 1.39	unconstrained · MANE · 2,716 bp · p 1.1e-11 · regional, not allelic
Overall
CADD	20.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.169% Middle Eastern · 10/5,914 alleles

Filtering AF 0.0917% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0698%

Overall 0.0221% 357/1,613,796 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.169%	591
Ashkenazi Jewishnot grpmax-eligible	0.135%	740
African / African-American	0.052%	1,923
Remaining individualsnot grpmax-eligible	0.0416%	2,403
East Asian	0.0223%	4,487
European (non-Finnish)	0.0189%	5,291
Admixed American	0.00833%	12,002
South Asian	0.00439%	22,762

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.Val217Ile
Coding: c.649G>A
MANE Select: NM_001836
dbSNP: rs143164371
Type: single nucleotide variant
Location: chr14:24505611 (GRCh38)
Gene constraint: LOEUF 1.578 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.55 · 42 PDB
Residue 217: 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.Val217Leu Uncertain significance ★ ⚠ same residue
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

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-val217ile (accessed [today's date]).

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