Is CMTR2 p.Ala16Pro (c.46G>C) pathogenic?

CMTR2 p.Ala16Pro (c.46G>C) is classified Uncertain significance in CMTR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-26). AlphaMissense: likely benign (0.0935); Ultra-rare (popmax 0.0101%, amr).

How common is CMTR2 p.Ala16Pro (c.46G>C) in the general population?

CMTR2 p.Ala16Pro (c.46G>C) is ultra-rare (popmax 0.0101%, amr) (gnomAD).

What do computational predictors say about CMTR2 p.Ala16Pro (c.46G>C)?

AlphaMissense predicts likely benign (score 0.0935) — an in-silico prediction, not a clinical call.

CMTR2 p.Ala16Pro

c.46G>C · VCV3834349

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0935 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0101%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0935	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -6.00	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 2.3	GERP -0.76, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 2,309 bp · p 0.74 · regional, not allelic
Overall
CADD	6.291	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

Grpmax group 0.0101% Admixed American · 6/59,292 alleles

Filtering AF 0.00433% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00298%

Overall 0.000412% 6/1,457,554 alleles · ultra-rare

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.Ala16Pro
Coding: c.46G>C
MANE Select: NM_018348
Type: single nucleotide variant
Location: chr16:71285875 (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.Ala16Thr Uncertain significance ★ ⚠ same residue
CMTR2 p.Ala16Val Uncertain significance ★ ⚠ same residue
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
CMTR2 p.Arg162Gln 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-ala16pro (accessed [today's date]).

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