Is CEP89 p.Val398Ala (c.1193T>C) pathogenic?

CEP89 p.Val398Ala (c.1193T>C) is classified Benign in CEP89 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.2328); Common (popmax 53.8%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CEP89 p.Val398Ala (c.1193T>C)?

AlphaMissense predicts likely benign (score 0.2328) — an in-silico prediction, not a clinical call.

CEP89 p.Val398Ala

Q: How common is CEP89 p.Val398Ala (c.1193T>C) in the general population?

CEP89 p.Val398Ala (c.1193T>C) is common (popmax 53.8%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1193T>C · rs4805825 · VCV1628429

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2328 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 53.8%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2328	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -6.66	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 3.3	GERP 1.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 93 kb · p 0.011 · regional, not allelic
Overall
CADD	20.5	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 53.8% East Asian · 24,026/44,696 alleles

Filtering AF 53.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 53%

Overall 20.7% 331,628/1,599,812 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	53.8%	2
Admixed American	25.2%	4
South Asian	23.6%	4
Amishnot grpmax-eligible	23.6%	4
Ashkenazi Jewishnot grpmax-eligible	21.6%	5
Remaining individualsnot grpmax-eligible	21.3%	5
African / African-American	20.4%	5
Middle Eastern	19.7%	5
Finnishnot grpmax-eligible	19.1%	5
European (non-Finnish)	19.1%	5

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.Val398Ala
Coding: c.1193T>C
MANE Select: NM_032816
dbSNP: rs4805825
Type: single nucleotide variant
Location: chr19:32923514 (GRCh38)
Gene constraint: LOEUF 1.173 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.08
Residue 398: a UniProt-annotated variant site (in)

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-val398ala (accessed [today's date]).

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