Is CNMD p.Pro15Ser (c.43C>T) pathogenic?

CNMD p.Pro15Ser (c.43C>T) is classified Uncertain significance in CNMD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely benign (0.1041); Ultra-rare (popmax 0.0164%, mid).

How common is CNMD p.Pro15Ser (c.43C>T) in the general population?

CNMD p.Pro15Ser (c.43C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CNMD p.Pro15Ser (c.43C>T)?

AlphaMissense predicts likely benign (score 0.1041) — an in-silico prediction, not a clinical call.

CNMD p.Pro15Ser

c.43C>T · rs752832077 · VCV3146507

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1041 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1041	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -5.64	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 8.3	GERP 0.55, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 36 kb · p 0.21 · regional, not allelic
Overall
CADD	19.95	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00161% 26/1,614,030 alleles · ultra-rare exomes 25/1,461,846 · genomes 1/152,184 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.00667%	15,001
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)	0.00153%	65,556
African / African-American	0.00133%	74,936

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: CNMD
Protein: p.Pro15Ser
Coding: c.43C>T
MANE Select: NM_007015
dbSNP: rs752832077
Type: single nucleotide variant
Location: chr13:52739659 (GRCh38)
Gene constraint: LOEUF 1.225 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.72

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

Similar variants

CNMD p.Val45= Benign ★★ same type
CNMD p.Ala112Thr Uncertain significance ★ ⚠ same type
CNMD p.Ala139Val Uncertain significance ★ ⚠ same type
CNMD p.Ala44Thr Uncertain significance ★ ⚠ same type
CNMD p.Ala94Thr Uncertain significance ★ ⚠ same type
CNMD p.Arg124His Uncertain significance ★ ⚠ same type
CNMD p.Arg140Cys Uncertain significance ★ ⚠ same type
CNMD p.Arg211Lys 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/cnmd-p-pro15ser (accessed [today's date]).

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