Is CMAS p.Arg175Cys (c.523C>T) pathogenic?

CMAS p.Arg175Cys (c.523C>T) is classified Uncertain significance in CMAS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-09). AlphaMissense: likely pathogenic (0.6755); Very rare (popmax 0.00935%, afr).

How common is CMAS p.Arg175Cys (c.523C>T) in the general population?

CMAS p.Arg175Cys (c.523C>T) is very rare (popmax 0.00935%, afr) (gnomAD).

What do computational predictors say about CMAS p.Arg175Cys (c.523C>T)?

AlphaMissense predicts likely pathogenic (score 0.6755) — an in-silico prediction, not a clinical call.

CMAS p.Arg175Cys

c.523C>T · rs371050975 · VCV2294344

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6755 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00935%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6755	likely pathogenic
REVEL	0.737	pathogenic-leaning
SaProt	LLR -9.79	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 6,214 bp · p 4.4e-12 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 0.00935% African / African-American · 7/74,894 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00112% 18/1,610,152 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00935%	10,699
East Asian	0.00223%	44,780
South Asian	0.00112%	89,598
European (non-Finnish)	0.000763%	131,016

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.Arg175Cys
Coding: c.523C>T
MANE Select: NM_018686
dbSNP: rs371050975
Type: single nucleotide variant
Location: chr12:22055574 (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.Arg175His Uncertain significance ★ ⚠ same residue
CMAS p.Lys26= Benign ★★ same type
CMAS p.Tyr403= Benign/Likely benign ★★ same type
CMAS p.Ala328Pro 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
CMAS p.Arg415Gln 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-arg175cys (accessed [today's date]).

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