Is CNNM2 p.Arg38Trp (c.112C>T) pathogenic?

CNNM2 p.Arg38Trp (c.112C>T) is classified Uncertain significance in CNNM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-06-07). AlphaMissense: likely benign (0.1508); Very rare (popmax 0.000345%, nfe); Associated with CNNM2-related disorder.

What condition is associated with CNNM2 p.Arg38Trp (c.112C>T)?

CNNM2 p.Arg38Trp (c.112C>T) is associated with CNNM2-related disorder (ClinVar).

How common is CNNM2 p.Arg38Trp (c.112C>T) in the general population?

CNNM2 p.Arg38Trp (c.112C>T) is very rare (popmax 0.000345%, nfe) (gnomAD).

What do computational predictors say about CNNM2 p.Arg38Trp (c.112C>T)?

AlphaMissense predicts likely benign (score 0.1508) — an in-silico prediction, not a clinical call.

CNNM2 p.Arg38Trp

c.112C>T · rs1480720023 · VCV2633481

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1508 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000345%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CNNM2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1508	likely benign
REVEL	0.325	indeterminate
SaProt	LLR -8.06	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 3.1	GERP 0.78, phastCons 1
Regional constraint	o/e 1.33	unconstrained · MANE · 150 bp · p 0.0044 · regional, not allelic
Overall
CADD	26.1	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 0.000345% European (non-Finnish) · 4/1,160,088 alleles

Filtering AF 8.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000283% 4/1,414,884 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: CNNM2
Protein: p.Arg38Trp
Coding: c.112C>T
MANE Select: NM_017649
dbSNP: rs1480720023
Type: single nucleotide variant
Location: chr10:102918592 (GRCh38)
Gene constraint: LOEUF 0.312 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.70 · 7 PDB
Residue 38: a UniProt-annotated variant site (in)

Full CNNM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CNNM2-related disorder

Similar variants

CNNM2 p.Arg38Gln Benign ★★ ⚠ same residue
CNNM2 p.Lys667Arg Uncertain significance ★ ⚠ same condition
CNNM2 p.Ser273Ile Uncertain significance ★ ⚠ same condition
CNNM2 p.Glu174Val Uncertain significance ⚠ same condition
CNNM2 c.1904-6C>A Likely benign same condition
NT5C2 p.Val512= Likely benign same condition
CNNM2 p.Arg47fs Likely pathogenic ★ same condition
CNNM2 p.Glu646fs Pathogenic ★ same condition

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/cnnm2-p-arg38trp (accessed [today's date]).

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