Is CEMIP2 p.Thr326Pro (c.976A>C) pathogenic?

CEMIP2 p.Thr326Pro (c.976A>C) is classified Uncertain significance in CEMIP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: ambiguous (0.453); Very rare (popmax 0.00169%, nfe); Associated with congenital heart disease.

What condition is associated with CEMIP2 p.Thr326Pro (c.976A>C)?

CEMIP2 p.Thr326Pro (c.976A>C) is associated with congenital heart disease (ClinVar).

How common is CEMIP2 p.Thr326Pro (c.976A>C) in the general population?

CEMIP2 p.Thr326Pro (c.976A>C) is very rare (popmax 0.00169%, nfe) (gnomAD).

What do computational predictors say about CEMIP2 p.Thr326Pro (c.976A>C)?

AlphaMissense predicts ambiguous (score 0.453) — an in-silico prediction, not a clinical call.

CEMIP2 p.Thr326Pro

c.976A>C · VCV4075819

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.453 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, nfe)

Conditions

congenital heart disease

Computational evidence

Protein change
AlphaMissense	0.453	ambiguous
REVEL	0.64	indeterminate
SaProt	LLR -11.40	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 65 kb · p 0.015 · regional, not allelic
Overall
CADD	22.6	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 0.00169% European (non-Finnish) · 20/1,180,010 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00124% 20/1,614,046 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: CEMIP2
Protein: p.Thr326Pro
Coding: c.976A>C
MANE Select: NM_013390
Type: single nucleotide variant
Location: chr9:71745076 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.66 · 1 PDB
Residue 326: the gg-type lectin 1 domain; an α-helix

Full CEMIP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital heart disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CEMIP2 p.Gly8Arg Uncertain significance ★ ⚠ same condition
CEMIP2 p.Leu322Val Uncertain significance ★ ⚠ same condition
CEMIP2 p.Met1Ile Uncertain significance ★ same condition
CEMIP2 p.Thr148Ser Uncertain significance ★ ⚠ same condition
CEMIP2 p.Asp164Val Uncertain significance ★★ ⚠ same type
CEMIP2 p.Cys453Tyr Pathogenic ★ same type
CEMIP2 p.Trp1048Ter Pathogenic ★ same type
CEMIP2 c.2399+1G>A 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/cemip2-p-thr326pro (accessed [today's date]).

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