Is CPM p.Pro411Ser (c.1231C>T) pathogenic?

CPM p.Pro411Ser (c.1231C>T) is classified Uncertain significance in CPM (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-27). AlphaMissense: likely benign (0.1159); Ultra-rare (popmax 0.0223%, eas).

How common is CPM p.Pro411Ser (c.1231C>T) in the general population?

CPM p.Pro411Ser (c.1231C>T) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about CPM p.Pro411Ser (c.1231C>T)?

AlphaMissense predicts likely benign (score 0.1159) — an in-silico prediction, not a clinical call.

CPM p.Pro411Ser

c.1231C>T · rs778304935 · VCV3076721

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1159 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1159	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -6.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 76 kb · p 2.5e-06 · regional, not allelic
Overall
CADD	19.66	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 0.0223% East Asian · 10/44,904 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00916%

Overall 0.000805% 13/1,614,100 alleles · ultra-rare exomes 11/1,461,884 · genomes 2/152,216 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,490
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.000169%	590,023

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.Pro411Ser
Coding: c.1231C>T
MANE Select: NM_198320
dbSNP: rs778304935
Type: single nucleotide variant
Location: chr12:68856538 (GRCh38)
Gene constraint: LOEUF 1.017 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.49 · 1 PDB

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

Similar variants

CPM p.Ala209Ser Uncertain significance ★ ⚠ same type
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

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-pro411ser (accessed [today's date]).

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