Is CMTR2 p.Arg635Trp (c.1903C>T) pathogenic?

CMTR2 p.Arg635Trp (c.1903C>T) is classified Uncertain significance in CMTR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: likely benign (0.0971); Rare (popmax 0.459%, eas).

How common is CMTR2 p.Arg635Trp (c.1903C>T) in the general population?

CMTR2 p.Arg635Trp (c.1903C>T) is rare (popmax 0.459%, eas) (gnomAD).

What do computational predictors say about CMTR2 p.Arg635Trp (c.1903C>T)?

AlphaMissense predicts likely benign (score 0.0971) — an in-silico prediction, not a clinical call.

CMTR2 p.Arg635Trp

c.1903C>T · VCV4654758

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0971 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.459%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0971	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -10.09	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	GERP 1.3, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 2,309 bp · p 0.74 · regional, not allelic
Overall
CADD	24.3	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 0.459% East Asian · 206/44,878 alleles

Filtering AF 0.408% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.388%

Overall 0.0261% 422/1,613,848 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.459%	218
African / African-American	0.159%	631
Remaining individualsnot grpmax-eligible	0.0448%	2,232
South Asian	0.0318%	3,140
Admixed American	0.02%	5,002
Middle Eastern	0.0165%	6,058
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
European (non-Finnish)	0.0022%	45,376

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: CMTR2
Protein: p.Arg635Trp
Coding: c.1903C>T
MANE Select: NM_018348
Type: single nucleotide variant
Location: chr16:71284018 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.01

Full CMTR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CMTR2 p.Arg635Gln Likely benign ★ same residue
CMTR2 p.Ala16Pro Uncertain significance ★ ⚠ same type
CMTR2 p.Ala16Thr Uncertain significance ★ ⚠ same type
CMTR2 p.Ala16Val Uncertain significance ★ ⚠ same type
CMTR2 p.Ala262Ser Uncertain significance ★ ⚠ same type
CMTR2 p.Ala31Ser Uncertain significance ★ ⚠ same type
CMTR2 p.Ala388Val Uncertain significance ★ ⚠ same type
CMTR2 p.Ala530Gly 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/cmtr2-p-arg635trp (accessed [today's date]).

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