Is CNNM4 p.Thr671Ile (c.2012C>T) pathogenic?

CNNM4 p.Thr671Ile (c.2012C>T) is classified Uncertain significance in CNNM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-31). AlphaMissense: likely benign (0.1117); Very rare (popmax 0.00329%, sas).

How common is CNNM4 p.Thr671Ile (c.2012C>T) in the general population?

CNNM4 p.Thr671Ile (c.2012C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about CNNM4 p.Thr671Ile (c.2012C>T)?

AlphaMissense predicts likely benign (score 0.1117) — an in-silico prediction, not a clinical call.

CNNM4 p.Thr671Ile

c.2012C>T · rs774886052 · VCV970059

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1117 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1117	likely benign
REVEL	0.027	moderately benign-leaning
SaProt	LLR -7.43	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 0.11	GERP -1.8
Regional constraint	o/e 0.82	unconstrained · MANE · 12 kb · p 0.00035 · regional, not allelic
Overall
CADD	5.033	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 0.00329% South Asian · 3/91,092 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000248% 4/1,614,036 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,364
European (non-Finnish)	8.47e-05%	1,180,016

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.Thr671Ile
Coding: c.2012C>T
MANE Select: NM_020184
dbSNP: rs774886052
Type: single nucleotide variant
Location: chr2:96808624 (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-thr671ile (accessed [today's date]).

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