Is CEP135 p.Arg331Ser (c.993A>T) pathogenic?

CEP135 p.Arg331Ser (c.993A>T) is classified Conflicting classifications of pathogenicity in CEP135 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-03-25). AlphaMissense: ambiguous (0.3524); Rare (popmax 0.231%, mid); Associated with microcephaly 8, primary, autosomal recessive.

What condition is associated with CEP135 p.Arg331Ser (c.993A>T)?

CEP135 p.Arg331Ser (c.993A>T) is associated with microcephaly 8, primary, autosomal recessive (ClinVar).

How common is CEP135 p.Arg331Ser (c.993A>T) in the general population?

CEP135 p.Arg331Ser (c.993A>T) is rare (popmax 0.231%, mid) (gnomAD).

What do computational predictors say about CEP135 p.Arg331Ser (c.993A>T)?

AlphaMissense predicts ambiguous (score 0.3524) — an in-silico prediction, not a clinical call.

CEP135 p.Arg331Ser

c.993A>T · rs140748251 · VCV694015

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3524 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.231%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

microcephaly 8, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.3524	ambiguous
REVEL	0.224	benign-leaning
SaProt	LLR -7.91	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 72 kb · p 0.83 · regional, not allelic
Overall
CADD	18.09	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 0.231% Middle Eastern · 14/6,058 alleles

Filtering AF 0.14% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.112%

Overall 0.0268% 433/1,613,814 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.231%	433
Admixed American	0.0466%	2,144
European (non-Finnish)	0.031%	3,224
Remaining individualsnot grpmax-eligible	0.0288%	3,472
African / African-American	0.008%	12,507
South Asian	0.0011%	91,054

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.Arg331Ser
Coding: c.993A>T
MANE Select: NM_025009
dbSNP: rs140748251
Type: single nucleotide variant
Location: chr4:55965808 (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

microcephaly 8, primary, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CEP135 p.Arg331Thr Uncertain significance ★ ⚠ same residue
CEP135 c.473-1G>C Likely pathogenic ★★ same condition
CEP135 p.Arg1083Ter Pathogenic/Likely pathogenic ★★ same condition
CEP135 p.Arg292Ter Pathogenic/Likely pathogenic ★★ same condition
CEP135 p.Arg418Ter Pathogenic ★★ same condition
CEP135 p.Arg470Ter Pathogenic/Likely pathogenic ★★ same condition
CEP135 p.Arg908Ter Pathogenic ★★ same condition
CEP135 p.Lys1071Ter Pathogenic/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/cep135-p-arg331ser (accessed [today's date]).

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