Is CMAS p.Asp249Glu (c.747T>A) pathogenic?

CMAS p.Asp249Glu (c.747T>A) is classified Uncertain significance in CMAS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-22). AlphaMissense: likely pathogenic (0.9974); Very rare (popmax 0.000424%, nfe).

How common is CMAS p.Asp249Glu (c.747T>A) in the general population?

CMAS p.Asp249Glu (c.747T>A) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about CMAS p.Asp249Glu (c.747T>A)?

AlphaMissense predicts likely pathogenic (score 0.9974) — an in-silico prediction, not a clinical call.

CMAS p.Asp249Glu

c.747T>A · VCV4003998

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9974 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9974	likely pathogenic · top 2% in CMAS
REVEL	0.468	indeterminate
SaProt	LLR -11.46	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 -1.2	GERP -1.5, phastCons 0.001
Regional constraint	o/e 0.56	unconstrained · MANE · 6,214 bp · p 4.4e-12 · regional, not allelic
Overall
CADD	21.2	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 0.000424% European (non-Finnish) · 5/1,178,424 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,459,872 alleles · very rare

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: CMAS
Protein: p.Asp249Glu
Coding: c.747T>A
MANE Select: NM_018686
Type: single nucleotide variant
Location: chr12:22060885 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 88.10

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

Similar variants

CMAS p.Lys26= Benign ★★ same type
CMAS p.Tyr403= Benign/Likely benign ★★ same type
CMAS p.Ala328Pro Uncertain significance ★ ⚠ same type
CMAS p.Arg175Cys Uncertain significance ★ ⚠ same type
CMAS p.Arg175His Uncertain significance ★ ⚠ same type
CMAS p.Arg18Leu Uncertain significance ★ ⚠ same type
CMAS p.Arg203Cys Uncertain significance ★ ⚠ same type
CMAS p.Arg241Gln 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/cmas-p-asp249glu (accessed [today's date]).

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