Is CEP89 p.Pro22Leu (c.65C>T) pathogenic?

CEP89 p.Pro22Leu (c.65C>T) is classified Uncertain significance in CEP89 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-18). AlphaMissense: likely pathogenic (0.7923); Ultra-rare (popmax 0.0338%, mid).

How common is CEP89 p.Pro22Leu (c.65C>T) in the general population?

CEP89 p.Pro22Leu (c.65C>T) is ultra-rare (popmax 0.0338%, mid) (gnomAD).

What do computational predictors say about CEP89 p.Pro22Leu (c.65C>T)?

AlphaMissense predicts likely pathogenic (score 0.7923) — an in-silico prediction, not a clinical call.

CEP89 p.Pro22Leu

c.65C>T · rs777663094 · VCV2162022

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7923 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0338%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7923	likely pathogenic · top 5% in CEP89
REVEL	0.389	indeterminate
SaProt	LLR -6.29	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.26	acceptor gain · deltas
Pangolin	Δ0.32	gain · loss 0.12 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.7	GERP 1.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 93 kb · p 0.011 · regional, not allelic
Overall
CADD	32.0	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 0.0338% Middle Eastern · 2/5,922 alleles

Filtering AF 0.0182% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0152%

Overall 0.00359% 56/1,561,074 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0338%	2,961
African / African-American	0.0275%	3,638
Remaining individualsnot grpmax-eligible	0.00499%	20,023
European (non-Finnish)	0.00252%	39,685
Admixed American	0.00185%	54,084
South Asian	0.00119%	84,020

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.Pro22Leu
Coding: c.65C>T
MANE Select: NM_032816
dbSNP: rs777663094
Type: single nucleotide variant
Location: chr19:32966441 (GRCh38)
Gene constraint: LOEUF 1.173 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.08

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-pro22leu (accessed [today's date]).

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