Is CEP164 p.Arg998Pro (c.2993G>C) pathogenic?

CEP164 p.Arg998Pro (c.2993G>C) is classified Uncertain significance in CEP164 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-24). AlphaMissense: likely pathogenic (0.8152); Ultra-rare (popmax 0.0168%, mid); Associated with nephronophthisis 15.

What condition is associated with CEP164 p.Arg998Pro (c.2993G>C)?

CEP164 p.Arg998Pro (c.2993G>C) is associated with nephronophthisis 15 (ClinVar).

How common is CEP164 p.Arg998Pro (c.2993G>C) in the general population?

CEP164 p.Arg998Pro (c.2993G>C) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

How is Senior-Loken syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CEP164 p.Arg998Pro (c.2993G>C)?

AlphaMissense predicts likely pathogenic (score 0.8152) — an in-silico prediction, not a clinical call.

CEP164 p.Arg998Pro

c.2993G>C · rs562263740 · VCV2042725

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8152 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis 15

Computational evidence

Protein change
AlphaMissense	0.8152	likely pathogenic · top 5% in CEP164
REVEL	0.187	benign-leaning
SaProt	LLR -14.46	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.52	GERP -2.1, phastCons 0.003
Regional constraint	o/e 0.97	unconstrained · MANE · 74 kb · p 0.19 · regional, not allelic
Overall
CADD	16.69	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 0.0168% Middle Eastern · 1/5,948 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00155% 25/1,613,824 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,948
Remaining individualsnot grpmax-eligible	0.0064%	15,620
East Asian	0.00223%	44,888
European (non-Finnish)	0.00144%	69,413
African / African-American	0.00133%	74,926
South Asian	0.0011%	91,048

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: CEP164
Protein: p.Arg998Pro
Coding: c.2993G>C
MANE Select: NM_014956
dbSNP: rs562263740
Type: single nucleotide variant
Location: chr11:117395626 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.08 · 4 PDB

Full CEP164 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephronophthisis 15 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Senior-Loken syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

CEP164 p.Arg998Ter Pathogenic/Likely pathogenic ★★ same residue
CEP164 p.Arg998Leu Uncertain significance ★ ⚠ same residue
CEP164 p.Arg998Gln Uncertain significance ★ ⚠ same residue
CEP164 c.1234-2A>T Likely pathogenic ★★ same condition
CEP164 c.1724+1G>A Likely pathogenic ★★ same condition
CEP164 c.1934+1G>A Likely pathogenic ★★ same condition
CEP164 c.2361+1G>A Likely pathogenic ★★ same condition
CEP164 c.2493+1G>A Likely pathogenic ★★ same condition

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/cep164-p-arg998pro (accessed [today's date]).

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