Is CEP89 p.Arg691Trp (c.2071C>T) pathogenic?

CEP89 p.Arg691Trp (c.2071C>T) is classified Benign in CEP89 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1426); Common (popmax 14.3%, sas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CEP89 p.Arg691Trp (c.2071C>T)?

AlphaMissense predicts likely benign (score 0.1426) — an in-silico prediction, not a clinical call.

CEP89 p.Arg691Trp

Q: How common is CEP89 p.Arg691Trp (c.2071C>T) in the general population?

CEP89 p.Arg691Trp (c.2071C>T) is common (popmax 14.3%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2071C>T · rs34626245 · VCV1559859

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1426 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 14.3%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1426	likely benign
REVEL	0.153	moderately benign-leaning
SaProt	LLR -8.72	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 -1.1	GERP -3.7
Regional constraint	o/e 0.92	unconstrained · MANE · 93 kb · p 0.011 · regional, not allelic
Overall
CADD	17.71	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 14.3% South Asian · 12,878/89,748 alleles

Filtering AF 14.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 14.1%

Overall 6.11% 98,014/1,604,792 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	14.3%	7
Ashkenazi Jewishnot grpmax-eligible	12.9%	8
Middle Eastern	11.8%	8
African / African-American	8.41%	12
Remaining individualsnot grpmax-eligible	7.35%	14
Admixed American	6.12%	16
Amishnot grpmax-eligible	5.7%	18
European (non-Finnish)	5.37%	19
East Asian	4.11%	24
Finnishnot grpmax-eligible	1.7%	59

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.Arg691Trp
Coding: c.2071C>T
MANE Select: NM_032816
dbSNP: rs34626245
Type: single nucleotide variant
Location: chr19:32881908 (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.Arg691Gln 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-arg691trp (accessed [today's date]).

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