Is CNNM1 p.Ser459Arg (c.1377C>G) pathogenic?

CNNM1 p.Ser459Arg (c.1377C>G) is classified Uncertain significance in CNNM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: likely pathogenic (0.9606); Very rare (popmax 0.000848%, nfe).

How common is CNNM1 p.Ser459Arg (c.1377C>G) in the general population?

CNNM1 p.Ser459Arg (c.1377C>G) is very rare (popmax 0.000848%, nfe) (gnomAD).

What do computational predictors say about CNNM1 p.Ser459Arg (c.1377C>G)?

AlphaMissense predicts likely pathogenic (score 0.9606) — an in-silico prediction, not a clinical call.

CNNM1 p.Ser459Arg

c.1377C>G · VCV4654937

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9606 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000848%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9606	likely pathogenic
REVEL	0.553	indeterminate
SaProt	LLR -7.73	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -2.2, phastCons 0.001
Regional constraint	o/e 0.65	unconstrained · MANE · 32 kb · p 1.2e-12 · regional, not allelic
Overall
CADD	18.96	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000848% European (non-Finnish) · 10/1,179,938 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000684% 10/1,461,766 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: CNNM1
Protein: p.Ser459Arg
Coding: c.1377C>G
MANE Select: NM_020348
Type: single nucleotide variant
Location: chr10:99330764 (GRCh38)
Gene constraint: LOEUF 0.617 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 67.07
Residue 459: the cbs 1 domain

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-ser459arg (accessed [today's date]).

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