Is CEMIP2 p.Val996Ala (c.2987T>C) pathogenic?

CEMIP2 p.Val996Ala (c.2987T>C) is classified Uncertain significance in CEMIP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-11). AlphaMissense: likely pathogenic (0.6192); Very rare (popmax 8.48e-05%, nfe).

How common is CEMIP2 p.Val996Ala (c.2987T>C) in the general population?

CEMIP2 p.Val996Ala (c.2987T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CEMIP2 p.Val996Ala (c.2987T>C)?

AlphaMissense predicts likely pathogenic (score 0.6192) — an in-silico prediction, not a clinical call.

CEMIP2 p.Val996Ala

c.2987T>C · VCV3831466

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6192 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6192	likely pathogenic
REVEL	0.343	indeterminate
SaProt	LLR -7.45	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 6.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 65 kb · p 0.015 · regional, not allelic
Overall
CADD	27.0	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 8.48e-05% European (non-Finnish) · 1/1,178,614 alleles

Overall 6.85e-05% 1/1,460,110 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.Val996Ala
Coding: c.2987T>C
MANE Select: NM_013390
Type: single nucleotide variant
Location: chr9:71704802 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.66 · 1 PDB
Residue 996: a β-strand

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

Similar variants

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
CEMIP2 p.Ala1134Gly Uncertain significance ★ ⚠ same type
CEMIP2 p.Ala1168Val Uncertain significance ★ ⚠ same type
CEMIP2 p.Ala186Val Uncertain significance ★ ⚠ same type
CEMIP2 p.Ala191Gly 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-val996ala (accessed [today's date]).

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