Is CEP89 p.Leu554Ser (c.1661T>C) pathogenic?

CEP89 p.Leu554Ser (c.1661T>C) is classified Likely benign in CEP89 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.1495); Rare (popmax 0.551%, nfe).

How common is CEP89 p.Leu554Ser (c.1661T>C) in the general population?

CEP89 p.Leu554Ser (c.1661T>C) is rare (popmax 0.551%, nfe) (gnomAD).

What do computational predictors say about CEP89 p.Leu554Ser (c.1661T>C)?

AlphaMissense predicts likely benign (score 0.1495) — an in-silico prediction, not a clinical call.

CEP89 p.Leu554Ser

c.1661T>C · rs148506114 · VCV1617636

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1495 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.551%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1495	likely benign
REVEL	0.362	indeterminate
SaProt	LLR -5.84	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 0.94
Regional constraint	o/e 0.92	unconstrained · MANE · 93 kb · p 0.011 · regional, not allelic
Overall
CADD	22.7	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 0.551% European (non-Finnish) · 6,498/1,180,022 alleles

Filtering AF 0.539% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.535%

Overall 0.438% 7,078/1,614,150 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.551%	182
Admixed American	0.372%	269
Remaining individualsnot grpmax-eligible	0.338%	296
African / African-American	0.104%	962
Middle Eastern	0.066%	1,516
South Asian	0.0472%	2,118
Ashkenazi Jewishnot grpmax-eligible	0.0439%	2,278
Finnishnot grpmax-eligible	0.0125%	8,003

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.Leu554Ser
Coding: c.1661T>C
MANE Select: NM_032816
dbSNP: rs148506114
Type: single nucleotide variant
Location: chr19:32901317 (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-leu554ser (accessed [today's date]).

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