Is CEP135 p.Arg435Cys (c.1303C>T) pathogenic?

CEP135 p.Arg435Cys (c.1303C>T) is classified Uncertain significance in CEP135 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-12). AlphaMissense: likely benign (0.1385); Very rare (popmax 0.00401%, afr); Associated with Inborn genetic diseases.

What condition is associated with CEP135 p.Arg435Cys (c.1303C>T)?

CEP135 p.Arg435Cys (c.1303C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CEP135 p.Arg435Cys (c.1303C>T) in the general population?

CEP135 p.Arg435Cys (c.1303C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about CEP135 p.Arg435Cys (c.1303C>T)?

AlphaMissense predicts likely benign (score 0.1385) — an in-silico prediction, not a clinical call.

CEP135 p.Arg435Cys

c.1303C>T · rs762126710 · VCV2238748

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1385 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1385	likely benign
REVEL	0.139	moderately benign-leaning
SaProt	LLR -8.35	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	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 72 kb · p 0.83 · regional, not allelic
Overall
CADD	26.3	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 0.00401% African / African-American · 3/74,866 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00211% 34/1,613,670 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,955
European (non-Finnish)	0.00246%	40,684
Remaining individualsnot grpmax-eligible	0.0016%	62,470
South Asian	0.0011%	91,068

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: CEP135
Protein: p.Arg435Cys
Coding: c.1303C>T
MANE Select: NM_025009
dbSNP: rs762126710
Type: single nucleotide variant
Location: chr4:55974799 (GRCh38)
Gene constraint: LOEUF 0.989 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.15 · 2 PDB

Full CEP135 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CEP135 p.Leu578Ter Pathogenic ★★ same condition
CEP135 c.2617-3C>T Uncertain significance ★★ same condition
CEP135 p.Ala1038Gly Uncertain significance ★★ ⚠ same condition
CEP135 p.Arg1116Gln Uncertain significance ★★ ⚠ same condition
CEP135 p.Arg168Cys Uncertain significance ★★ ⚠ same condition
CEP135 p.Arg252Trp Uncertain significance ★★ ⚠ same condition
CEP135 p.Arg442His Uncertain significance ★★ ⚠ same condition
CEP135 p.Arg454Gly Uncertain significance ★★ ⚠ 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/cep135-p-arg435cys (accessed [today's date]).

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