Is CEMIP2 p.Thr89Ile (c.266C>T) pathogenic?

CEMIP2 p.Thr89Ile (c.266C>T) is classified Uncertain significance in CEMIP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-28). AlphaMissense: ambiguous (0.3642); Very rare (popmax 0.00119%, nfe).

How common is CEMIP2 p.Thr89Ile (c.266C>T) in the general population?

CEMIP2 p.Thr89Ile (c.266C>T) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about CEMIP2 p.Thr89Ile (c.266C>T)?

AlphaMissense predicts ambiguous (score 0.3642) — an in-silico prediction, not a clinical call.

CEMIP2 p.Thr89Ile

c.266C>T · rs1209668488 · VCV3142177

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3642 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3642	ambiguous
REVEL	0.128	moderately benign-leaning
SaProt	LLR -5.66	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 65 kb · p 0.015 · regional, not allelic
Overall
CADD	23.5	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 0.00119% European (non-Finnish) · 14/1,179,914 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00149% 24/1,613,670 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0125%	8,001
Remaining individualsnot grpmax-eligible	0.0032%	31,236
European (non-Finnish)grpmax	0.00119%	84,279

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr89Ile
Coding: c.266C>T
MANE Select: NM_013390
dbSNP: rs1209668488
Type: single nucleotide variant
Location: chr9:71750108 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.66 · 1 PDB

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-thr89ile (accessed [today's date]).

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