Is CEP89 p.Arg194Trp (c.580C>T) pathogenic?

CEP89 p.Arg194Trp (c.580C>T) is classified Benign in CEP89 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0948); Common (popmax 22.4%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CEP89 p.Arg194Trp (c.580C>T)?

AlphaMissense predicts likely benign (score 0.0948) — an in-silico prediction, not a clinical call.

CEP89 p.Arg194Trp

Q: How common is CEP89 p.Arg194Trp (c.580C>T) in the general population?

CEP89 p.Arg194Trp (c.580C>T) is common (popmax 22.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.580C>T · rs3764633 · VCV1600807

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0948 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 22.4%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0948	likely benign
REVEL	0.166	moderately benign-leaning
SaProt	LLR -8.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1	GERP -4.3
Regional constraint	o/e 0.92	unconstrained · MANE · 93 kb · p 0.011 · regional, not allelic
Overall
CADD	9.091	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 22.4% African / African-American · 16,591/73,908 alleles

Filtering AF 22.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 22%

Overall 18.5% 294,562/1,589,486 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	24.5%	4
African / African-Americangrpmax	22.4%	4
Amishnot grpmax-eligible	21.6%	5
East Asian	20.6%	5
Middle Eastern	19.2%	5
Remaining individualsnot grpmax-eligible	19.1%	5
European (non-Finnish)	18.4%	5
Ashkenazi Jewishnot grpmax-eligible	17.9%	6
South Asian	16.8%	6
Admixed American	10.8%	9

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: CEP89
Protein: p.Arg194Trp
Coding: c.580C>T
MANE Select: NM_032816
dbSNP: rs3764633
Type: single nucleotide variant
Location: chr19:32948281 (GRCh38)
Gene constraint: LOEUF 1.173 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.08
Residue 194: a UniProt-annotated variant site (in); the 'disordered' region

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

Similar variants

CEP89 p.Arg194Gln Uncertain significance ★ ⚠ same residue
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

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-arg194trp (accessed [today's date]).

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