Is CPM p.Ala209Ser (c.625G>T) pathogenic?

CPM p.Ala209Ser (c.625G>T) is classified Uncertain significance in CPM (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-17). AlphaMissense: likely benign (0.0722); Very rare (popmax 8.52e-05%, nfe).

How common is CPM p.Ala209Ser (c.625G>T) in the general population?

CPM p.Ala209Ser (c.625G>T) is very rare (popmax 8.52e-05%, nfe) (gnomAD).

What do computational predictors say about CPM p.Ala209Ser (c.625G>T)?

AlphaMissense predicts likely benign (score 0.0722) — an in-silico prediction, not a clinical call.

CPM p.Ala209Ser

c.625G>T · rs1160392365 · VCV2326688

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0722 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.52e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0722	likely benign
REVEL	0.005	strongly benign-leaning
SaProt	LLR -2.43	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 -0.12	GERP -3.5, phastCons 0.001
Regional constraint	o/e 0.80	unconstrained · MANE · 76 kb · p 2.5e-06 · regional, not allelic
Overall
CADD	0.89	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 8.52e-05% European (non-Finnish) · 1/1,173,212 alleles

Overall 6.9e-05% 1/1,448,806 alleles · very 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: CPM
Protein: p.Ala209Ser
Coding: c.625G>T
MANE Select: NM_198320
dbSNP: rs1160392365
Type: single nucleotide variant
Location: chr12:68869487 (GRCh38)
Gene constraint: LOEUF 1.017 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.49 · 1 PDB
Residue 209: a disulfide bond; the peptidase m14 domain; an α-helix

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

Similar variants

CPM p.Ala36Thr Uncertain significance ★ ⚠ same type
CPM p.Arg118Gln Uncertain significance ★ ⚠ same type
CPM p.Arg213Gln Uncertain significance ★ ⚠ same type
CPM p.Arg289Cys Uncertain significance ★ ⚠ same type
CPM p.Arg289Gly Uncertain significance ★ ⚠ same type
CPM p.Arg289His Uncertain significance ★ ⚠ same type
CPM p.Asn299Ser Uncertain significance ★ ⚠ same type
CPM p.Asn300Lys 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/cpm-p-ala209ser (accessed [today's date]).

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