Is CEP295 p.Leu1969Pro (c.5906T>C) pathogenic?

CEP295 p.Leu1969Pro (c.5906T>C) is classified Uncertain significance in CEP295 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-25). AlphaMissense: likely benign (0.2546); Very rare (popmax 0.00607%, nfe).

How common is CEP295 p.Leu1969Pro (c.5906T>C) in the general population?

CEP295 p.Leu1969Pro (c.5906T>C) is very rare (popmax 0.00607%, nfe) (gnomAD).

What do computational predictors say about CEP295 p.Leu1969Pro (c.5906T>C)?

AlphaMissense predicts likely benign (score 0.2546) — an in-silico prediction, not a clinical call.

CEP295 p.Leu1969Pro

c.5906T>C · rs755406375 · VCV3142841

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2546 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00607%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2546	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -7.26	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 6.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 35 kb · p 0.4 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00607% European (non-Finnish) · 70/1,153,286 alleles

Filtering AF 0.00489% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00449%

Overall 0.00472% 74/1,567,260 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00607%	16,476
Remaining individualsnot grpmax-eligible	0.00329%	30,429
African / African-American	0.00272%	36,810

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.Leu1969Pro
Coding: c.5906T>C
MANE Select: NM_033395
dbSNP: rs755406375
Type: single nucleotide variant
Location: chr11:93722009 (GRCh38)
Gene constraint: LOEUF 0.735 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 44.76
Residue 1969: 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-leu1969pro (accessed [today's date]).

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