Is CMTR2 p.Ser225Arg (c.673A>C) pathogenic?

CMTR2 p.Ser225Arg (c.673A>C) is classified Uncertain significance in CMTR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-02). AlphaMissense: likely benign (0.138); Absent from gnomAD v4.1.

How common is CMTR2 p.Ser225Arg (c.673A>C) in the general population?

CMTR2 p.Ser225Arg (c.673A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CMTR2 p.Ser225Arg (c.673A>C)?

AlphaMissense predicts likely benign (score 0.138) — an in-silico prediction, not a clinical call.

CMTR2 p.Ser225Arg

c.673A>C · VCV3494191

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.138 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.138	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -7.10	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 -0.32	GERP -4.7
Regional constraint	o/e 1.01	unconstrained · MANE · 2,309 bp · p 0.74 · regional, not allelic
Overall
CADD	17.27	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CMTR2
Protein: p.Ser225Arg
Coding: c.673A>C
MANE Select: NM_018348
Type: single nucleotide variant
Location: chr16:71285248 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.01
Residue 225: the adrift-type sam-dependent 2'-o-mtase domain

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

Similar variants

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
CMTR2 p.Ala684Thr 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-ser225arg (accessed [today's date]).

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