Is CEP89 p.Pro33Leu (c.98C>T) pathogenic?

CEP89 p.Pro33Leu (c.98C>T) is classified Uncertain significance in CEP89 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-27). AlphaMissense: likely pathogenic (0.8397); Very rare (popmax 0.00217%, nfe).

How common is CEP89 p.Pro33Leu (c.98C>T) in the general population?

CEP89 p.Pro33Leu (c.98C>T) is very rare (popmax 0.00217%, nfe) (gnomAD).

What do computational predictors say about CEP89 p.Pro33Leu (c.98C>T)?

AlphaMissense predicts likely pathogenic (score 0.8397) — an in-silico prediction, not a clinical call.

CEP89 p.Pro33Leu

c.98C>T · rs1358071100 · VCV2601854

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8397 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00217%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8397	likely pathogenic · top 4% in CEP89
REVEL	0.338	indeterminate
SaProt	LLR -7.49	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 12	GERP 1.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 93 kb · p 0.011 · regional, not allelic
Overall
CADD	29.5	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 0.00217% European (non-Finnish) · 25/1,151,836 alleles

Filtering AF 0.00149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00126%

Overall 0.00173% 27/1,562,542 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00217%	46,073
Admixed American	0.00184%	54,362
Remaining individualsnot grpmax-eligible	0.00166%	60,078

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: CEP89
Protein: p.Pro33Leu
Coding: c.98C>T
MANE Select: NM_032816
dbSNP: rs1358071100
Type: single nucleotide variant
Location: chr19:32966408 (GRCh38)
Gene constraint: LOEUF 1.173 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.08
Residue 33: the 'disordered' region

Full CEP89 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CEP89 p.Ala291Thr Uncertain significance ★★ ⚠ same type
CEP89 p.Ala291Val Uncertain significance ★★ ⚠ same type
CEP89 p.Ala372Thr Uncertain significance ★★ ⚠ same type
CEP89 p.Ala54Val Uncertain significance ★★ ⚠ same type
CEP89 p.Ala680Thr Uncertain significance ★★ ⚠ same type
CEP89 p.Ala780Asp Uncertain significance ★★ ⚠ same type
CEP89 p.Arg102Trp Uncertain significance ★★ ⚠ same type
CEP89 p.Arg324Cys 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/cep89-p-pro33leu (accessed [today's date]).

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