Is CEP89 p.Arg397Ter (c.1189C>T) pathogenic?

CEP89 p.Arg397Ter (c.1189C>T) is classified Uncertain significance in CEP89 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-23). Ultra-rare (popmax 0.0308%, afr).

How common is CEP89 p.Arg397Ter (c.1189C>T) in the general population?

CEP89 p.Arg397Ter (c.1189C>T) is ultra-rare (popmax 0.0308%, afr) (gnomAD).

CEP89 p.Arg397Ter

c.1189C>T · rs374612024 · VCV1391653

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0308%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 19
Splicing
SpliceAI	Δ0.31	acceptor loss · deltas
Pangolin	Δ0.49	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.1	GERP 0.55, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0308% African / African-American · 23/74,732 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0178%

Overall 0.0025% 40/1,600,604 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0308%	3,249
Middle Eastern	0.0166%	6,038
Admixed American	0.00502%	19,937
East Asian	0.00447%	22,350
Remaining individualsnot grpmax-eligible	0.00322%	31,032
South Asian	0.0011%	90,528
European (non-Finnish)	0.000685%	146,050

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.Arg397Ter
Coding: c.1189C>T
MANE Select: NM_032816
dbSNP: rs374612024
Type: single nucleotide variant
Location: chr19:32923518 (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-arg397ter (accessed [today's date]).

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