Is CNNM1 p.Pro35Ser (c.103C>T) pathogenic?

CNNM1 p.Pro35Ser (c.103C>T) is classified Uncertain significance in CNNM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-20). AlphaMissense: likely benign (0.0971); Rare (popmax 0.133%, nfe).

How common is CNNM1 p.Pro35Ser (c.103C>T) in the general population?

CNNM1 p.Pro35Ser (c.103C>T) is rare (popmax 0.133%, nfe) (gnomAD).

What do computational predictors say about CNNM1 p.Pro35Ser (c.103C>T)?

AlphaMissense predicts likely benign (score 0.0971) — an in-silico prediction, not a clinical call.

CNNM1 p.Pro35Ser

c.103C>T · rs527685732 · VCV2306913

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0971 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.133%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0971	likely benign
REVEL	0.256	benign-leaning
SaProt	LLR -7.75	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 3.9	GERP 0.075, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,002 bp · p 0.7 · regional, not allelic
Overall
CADD	24.6	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 0.133% European (non-Finnish) · 1,500/1,123,626 alleles

Filtering AF 0.128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.126%

Overall 0.108% 1,623/1,496,668 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.133%	749
Middle Eastern	0.0922%	1,084
Remaining individualsnot grpmax-eligible	0.0703%	1,422
Finnishnot grpmax-eligible	0.0678%	1,475
Admixed American	0.0611%	1,636
African / African-American	0.0115%	8,661
South Asian	0.0075%	13,327
Ashkenazi Jewishnot grpmax-eligible	0.00728%	13,739

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: CNNM1
Protein: p.Pro35Ser
Coding: c.103C>T
MANE Select: NM_020348
dbSNP: rs527685732
Type: single nucleotide variant
Location: chr10:99329490 (GRCh38)
Gene constraint: LOEUF 0.617 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 67.07

Full CNNM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNNM1 c.1717+145G>A Benign ★★ same type
CNNM1 c.1858+55C>T Benign ★★ same type
CNNM1 c.2340+88G>A Benign ★★ same type
CNNM1 c.2776+92A>G Benign ★★ same type
CNNM1 p.Ala222= Benign ★★ same type
CNNM1 p.Arg819Gln Benign ★★ same type
CNNM1 p.Asp828= Benign ★★ same type
CNNM1 p.Val428= Benign ★★ 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/cnnm1-p-pro35ser (accessed [today's date]).

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