Is CNNM3 p.Pro163Ser (c.487C>T) pathogenic?

CNNM3 p.Pro163Ser (c.487C>T) is classified Uncertain significance in CNNM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-26). AlphaMissense: likely benign (0.215); Very rare (popmax 0.00523%, afr).

How common is CNNM3 p.Pro163Ser (c.487C>T) in the general population?

CNNM3 p.Pro163Ser (c.487C>T) is very rare (popmax 0.00523%, afr) (gnomAD).

What do computational predictors say about CNNM3 p.Pro163Ser (c.487C>T)?

AlphaMissense predicts likely benign (score 0.215) — an in-silico prediction, not a clinical call.

CNNM3 p.Pro163Ser

c.487C>T · VCV3494424

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.215 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00523%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.215	likely benign
REVEL	0.459	indeterminate
SaProt	LLR -9.76	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.8	GERP 1.3, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 849 bp · p 0.0017 · regional, not allelic
Overall
CADD	23.7	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 0.00523% African / African-American · 3/57,332 alleles

Filtering AF 0.00139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000685%

Overall 0.000785% 8/1,019,458 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00523%	19,111
South Asian	0.0044%	22,726
Remaining individualsnot grpmax-eligible	0.00317%	31,554
European (non-Finnish)	0.000351%	284,908

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: CNNM3
Protein: p.Pro163Ser
Coding: c.487C>T
MANE Select: NM_017623
Type: single nucleotide variant
Location: chr2:96816764 (GRCh38)
Gene constraint: LOEUF 1.23 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.63 · 7 PDB
Residue 163: the cnnm transmembrane domain

Full CNNM3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNNM3 p.Ala221Gly Uncertain significance ★★ ⚠ same type
CNNM3 p.Ala128Val Uncertain significance ★ ⚠ same type
CNNM3 p.Ala142Thr Uncertain significance ★ ⚠ same type
CNNM3 p.Ala146Val Uncertain significance ★ ⚠ same type
CNNM3 p.Ala158Thr Uncertain significance ★ ⚠ same type
CNNM3 p.Ala162Glu Uncertain significance ★ ⚠ same type
CNNM3 p.Ala176Thr Uncertain significance ★ ⚠ same type
CNNM3 p.Ala191Thr 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/cnnm3-p-pro163ser (accessed [today's date]).

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