Is CMTR1 p.Pro35Ser (c.103C>T) pathogenic?

CMTR1 p.Pro35Ser (c.103C>T) is classified Uncertain significance in CMTR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-19). AlphaMissense: likely benign (0.0674); Very rare (popmax 0.0018%, amr).

How common is CMTR1 p.Pro35Ser (c.103C>T) in the general population?

CMTR1 p.Pro35Ser (c.103C>T) is very rare (popmax 0.0018%, amr) (gnomAD).

What do computational predictors say about CMTR1 p.Pro35Ser (c.103C>T)?

AlphaMissense predicts likely benign (score 0.0674) — an in-silico prediction, not a clinical call.

CMTR1 p.Pro35Ser

c.103C>T · rs2481623402 · VCV2246530

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0674 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0018%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0674	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -5.12	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 5.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 8,480 bp · p 0.44 · regional, not allelic
Overall
CADD	20.9	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 0.0018% Admixed American · 1/55,678 alleles

Overall 0.000188% 3/1,597,400 alleles · very rare exomes 3/1,445,076 · genomes 0/152,324 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0018%	55,678
Finnishnot grpmax-eligible	0.00156%	63,918
South Asian	0.00114%	87,856

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: CMTR1
Protein: p.Pro35Ser
Coding: c.103C>T
MANE Select: NM_015050
dbSNP: rs2481623402
Type: single nucleotide variant
Location: chr6:37435732 (GRCh38)
Gene constraint: LOEUF 0.437 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.97 · 6 PDB
Residue 35: the 'disordered' region

Full CMTR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CMTR1 p.Pro35Leu Uncertain significance ★ ⚠ same residue
CMTR1 p.Ala217Gly Uncertain significance ★ same type
CMTR1 p.Ala462Glu Uncertain significance ★ ⚠ same type
CMTR1 p.Ala512Glu Uncertain significance ★ ⚠ same type
CMTR1 p.Arg144Gln Uncertain significance ★ ⚠ same type
CMTR1 p.Arg218Trp Uncertain significance ★ ⚠ same type
CMTR1 p.Arg249His Uncertain significance ★ ⚠ same type
CMTR1 p.Arg346Gln 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/cmtr1-p-pro35ser (accessed [today's date]).

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