Is CNNM4 p.Leu691Pro (c.2072T>C) pathogenic?

CNNM4 p.Leu691Pro (c.2072T>C) is classified Uncertain significance in CNNM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-13). AlphaMissense: likely benign (0.0767); Very rare (popmax 0.00415%, nfe).

How common is CNNM4 p.Leu691Pro (c.2072T>C) in the general population?

CNNM4 p.Leu691Pro (c.2072T>C) is very rare (popmax 0.00415%, nfe) (gnomAD).

What do computational predictors say about CNNM4 p.Leu691Pro (c.2072T>C)?

AlphaMissense predicts likely benign (score 0.0767) — an in-silico prediction, not a clinical call.

CNNM4 p.Leu691Pro

c.2072T>C · rs781192785 · VCV1063857

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0767 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00415%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0767	likely benign
REVEL	0.166	moderately benign-leaning
SaProt	LLR -5.23	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 3.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 12 kb · p 0.00035 · regional, not allelic
Overall
CADD	19.53	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 0.00415% European (non-Finnish) · 49/1,180,038 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.00342% 50/1,461,890 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00415%	24,082
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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: CNNM4
Protein: p.Leu691Pro
Coding: c.2072T>C
MANE Select: NM_020184
dbSNP: rs781192785
Type: single nucleotide variant
Location: chr2:96808684 (GRCh38)
Gene constraint: LOEUF 0.794 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.20 · 6 PDB

Full CNNM4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNNM4 p.Arg519Ter Pathogenic ★★ same type
CNNM4 p.Arg605Ter Pathogenic ★★ same type
CNNM4 p.Gln564Ter Pathogenic ★★ same type
CNNM4 p.Gln717Ter Pathogenic/Likely pathogenic ★★ same type
CNNM4 c.2130+5G>A Uncertain significance ★★ same type
CNNM4 c.*1126G>A Uncertain significance ★★ same type
CNNM4 p.Ala297Gly Uncertain significance ★★ ⚠ same type
CNNM4 p.Ala35Thr 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/cnnm4-p-leu691pro (accessed [today's date]).

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