Is CEP89 p.Pro41Thr (c.121C>A) pathogenic?

CEP89 p.Pro41Thr (c.121C>A) is classified Uncertain significance in CEP89 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-20). AlphaMissense: ambiguous (0.5568); Very rare (popmax 0.00921%, amr).

How common is CEP89 p.Pro41Thr (c.121C>A) in the general population?

CEP89 p.Pro41Thr (c.121C>A) is very rare (popmax 0.00921%, amr) (gnomAD).

What do computational predictors say about CEP89 p.Pro41Thr (c.121C>A)?

AlphaMissense predicts ambiguous (score 0.5568) — an in-silico prediction, not a clinical call.

CEP89 p.Pro41Thr

c.121C>A · VCV3266287

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5568 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00921%, amr)

Computational evidence

Protein change
AlphaMissense	0.5568	ambiguous
REVEL	0.413	indeterminate
SaProt	LLR -8.14	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 93 kb · p 0.011 · regional, not allelic
Overall
CADD	27.7	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 0.00921% Admixed American · 5/54,314 alleles

Filtering AF 0.00353% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00235%

Overall 0.00045% 7/1,557,218 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00921%	10,863
Remaining individualsnot grpmax-eligible	0.00167%	59,858
European (non-Finnish)	8.71e-05%	1,148,139

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.Pro41Thr
Coding: c.121C>A
MANE Select: NM_032816
Type: single nucleotide variant
Location: chr19:32966385 (GRCh38)
Gene constraint: LOEUF 1.173 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.08
Residue 41: 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-pro41thr (accessed [today's date]).

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