Is CMSS1 p.Ile192Arg (c.575T>G) pathogenic?

CMSS1 p.Ile192Arg (c.575T>G) is classified Uncertain significance in CMSS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-26). AlphaMissense: ambiguous (0.4023); Very rare (popmax 0.00133%, afr).

How common is CMSS1 p.Ile192Arg (c.575T>G) in the general population?

CMSS1 p.Ile192Arg (c.575T>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CMSS1 p.Ile192Arg (c.575T>G)?

AlphaMissense predicts ambiguous (score 0.4023) — an in-silico prediction, not a clinical call.

CMSS1 p.Ile192Arg

c.575T>G · VCV3494144

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4023 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Computational evidence

Protein change
AlphaMissense	0.4023	ambiguous
REVEL	0.405	indeterminate
SaProt	LLR -12.17	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 360 kb · p 0.46 · regional, not allelic
Overall
CADD	25.7	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

Grpmax group 0.00133% African / African-American · 1/74,922 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.00062% 10/1,613,374 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,922
European (non-Finnish)	0.000763%	131,056

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: CMSS1
Protein: p.Ile192Arg
Coding: c.575T>G
MANE Select: NM_032359
Type: single nucleotide variant
Location: chr3:100171895 (GRCh38)
Gene constraint: LOEUF 1.021 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.31

Full CMSS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CMSS1 p.Ala83Gly Uncertain significance ★ ⚠ same type
CMSS1 p.Arg107Cys Uncertain significance ★ ⚠ same type
CMSS1 p.Arg107His Uncertain significance ★ ⚠ same type
CMSS1 p.Arg204Cys Uncertain significance ★ ⚠ same type
CMSS1 p.Arg204Ser Uncertain significance ★ ⚠ same type
CMSS1 p.Asp94Gly Uncertain significance ★ ⚠ same type
CMSS1 p.Cys121Arg Uncertain significance ★ ⚠ same type
CMSS1 p.Glu138Gln 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/cmss1-p-ile192arg (accessed [today's date]).

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