Is CNNM2 p.Pro744Leu (c.2231C>T) pathogenic?

CNNM2 p.Pro744Leu (c.2231C>T) is classified Uncertain significance in CNNM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-04-24). AlphaMissense: likely benign (0.0947); Absent from gnomAD v4.1; Associated with intellectual disability.

What condition is associated with CNNM2 p.Pro744Leu (c.2231C>T)?

CNNM2 p.Pro744Leu (c.2231C>T) is associated with intellectual disability (ClinVar).

How common is CNNM2 p.Pro744Leu (c.2231C>T) in the general population?

CNNM2 p.Pro744Leu (c.2231C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNNM2 p.Pro744Leu (c.2231C>T)?

AlphaMissense predicts likely benign (score 0.0947) — an in-silico prediction, not a clinical call.

CNNM2 p.Pro744Leu

c.2231C>T · VCV4075108

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0947 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability

Computational evidence

Protein change
AlphaMissense	0.0947	likely benign
REVEL	0.224	benign-leaning
SaProt	LLR -6.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.40	donor loss · deltas
Pangolin	Δ0.44	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 8,525 bp · p 0.026 · regional, not allelic
Overall
CADD	31.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CNNM2
Protein: p.Pro744Leu
Coding: c.2231C>T
MANE Select: NM_017649
Type: single nucleotide variant
Location: chr10:103071837 (GRCh38)
Gene constraint: LOEUF 0.312 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.70 · 7 PDB
Residue 744: the 'disordered' region

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

Disease context

intellectual disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNNM2 p.Arg820Gln Uncertain significance ★ ⚠ same condition
CNNM2 p.Phe731Cys Uncertain significance ★ ⚠ same condition
CNNM2 p.Arg602Ter Likely pathogenic ★★ same type
CNNM2 p.Asn327Ser Likely pathogenic ★★ same type
CNNM2 p.Glu122Lys Pathogenic/Likely pathogenic ★★ same type
CNNM2 p.Glu357Lys Pathogenic ★★ same type
CNNM2 p.Ser269Trp Pathogenic/Likely pathogenic ★★ same type
CNNM2 c.1904-6C>G 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/cnnm2-p-pro744leu (accessed [today's date]).

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