Is CEP135 p.Pro157Ala (c.469C>G) pathogenic?

CEP135 p.Pro157Ala (c.469C>G) is classified Uncertain significance in CEP135 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-04). AlphaMissense: likely benign (0.3167); Very rare (popmax 0.00136%, afr); Associated with Inborn genetic diseases.

What condition is associated with CEP135 p.Pro157Ala (c.469C>G)?

CEP135 p.Pro157Ala (c.469C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CEP135 p.Pro157Ala (c.469C>G) in the general population?

CEP135 p.Pro157Ala (c.469C>G) is very rare (popmax 0.00136%, afr) (gnomAD).

What do computational predictors say about CEP135 p.Pro157Ala (c.469C>G)?

AlphaMissense predicts likely benign (score 0.3167) — an in-silico prediction, not a clinical call.

CEP135 p.Pro157Ala

c.469C>G · VCV3490529

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3167 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3167	likely benign
REVEL	0.317	indeterminate
SaProt	LLR -7.61	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.4, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 72 kb · p 0.83 · regional, not allelic
Overall
CADD	24.5	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 0.00136% African / African-American · 1/73,286 alleles

Filtering AF 0.000294% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000212%

Overall 0.00063% 10/1,586,846 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00157%	63,566
African / African-Americangrpmax	0.00136%	73,286
European (non-Finnish)	0.000683%	146,336

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro157Ala
Coding: c.469C>G
MANE Select: NM_025009
Type: single nucleotide variant
Location: chr4:55954380 (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.Pro157Leu Uncertain significance ★ ⚠ same residue
CEP135 p.Pro157= Uncertain significance ★ same residue
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

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-pro157ala (accessed [today's date]).

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