Is CEP295 p.Arg590Ser (c.1770G>C) pathogenic?

CEP295 p.Arg590Ser (c.1770G>C) is classified Uncertain significance in CEP295 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-06). AlphaMissense: likely pathogenic (0.6063); Very rare (popmax 0.00138%, afr).

How common is CEP295 p.Arg590Ser (c.1770G>C) in the general population?

CEP295 p.Arg590Ser (c.1770G>C) is very rare (popmax 0.00138%, afr) (gnomAD).

What do computational predictors say about CEP295 p.Arg590Ser (c.1770G>C)?

AlphaMissense predicts likely pathogenic (score 0.6063) — an in-silico prediction, not a clinical call.

CEP295 p.Arg590Ser

c.1770G>C · VCV4652444

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6063 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00138%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6063	likely pathogenic · top 5% in CEP295
REVEL	0.153	moderately benign-leaning
SaProt	LLR -7.16	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.24	acceptor loss at this position · masked 0 · deltas
Pangolin	Δ0.32	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.9	GERP 0.93, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 35 kb · p 0.4 · regional, not allelic
Overall
CADD	24.1	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 0.00138% African / African-American · 1/72,302 alleles

Overall 7.22e-05% 1/1,384,146 alleles · very rare

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: CEP295
Protein: p.Arg590Ser
Coding: c.1770G>C
MANE Select: NM_033395
Type: single nucleotide variant
Location: chr11:93696682 (GRCh38)
Gene constraint: LOEUF 0.735 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 44.76
Residue 590: a UniProt-annotated variant site (in sckl11; likely pathogenic)

Full CEP295 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CEP295 p.Gln2146His Uncertain significance ★★ ⚠ same type
CEP295 p.Gln998Arg Uncertain significance ★★ ⚠ same type
CEP295 p.Thr451Arg Uncertain significance ★★ ⚠ same type
CEP295 p.Gln1506= Benign ★★ same type
CEP295 p.Gln1728= Benign ★★ same type
CEP295 p.Gln80Lys Benign ★★ same type
CEP295 p.Glu1026Lys Benign ★★ ⚠ same type
CEP295 p.Glu179Lys Benign ★★ 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/cep295-p-arg590ser (accessed [today's date]).

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