Is CMTR2 p.Leu751Ser (c.2252T>C) pathogenic?

CMTR2 p.Leu751Ser (c.2252T>C) is classified Uncertain significance in CMTR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-03). AlphaMissense: likely pathogenic (0.8703); Absent from gnomAD v4.1.

How common is CMTR2 p.Leu751Ser (c.2252T>C) in the general population?

CMTR2 p.Leu751Ser (c.2252T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CMTR2 p.Leu751Ser (c.2252T>C)?

AlphaMissense predicts likely pathogenic (score 0.8703) — an in-silico prediction, not a clinical call.

CMTR2 p.Leu751Ser

c.2252T>C · VCV3834354

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8703 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8703	likely pathogenic · top 10% in CMTR2
REVEL	0.453	indeterminate
SaProt	LLR -8.35	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 2,309 bp · p 0.74 · regional, not allelic
Overall
CADD	25.0	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

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.Leu751Ser
Coding: c.2252T>C
MANE Select: NM_018348
Type: single nucleotide variant
Location: chr16:71283669 (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.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-leu751ser (accessed [today's date]).

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