Is CEP135 p.Met991Val (c.2971A>G) pathogenic?

CEP135 p.Met991Val (c.2971A>G) is classified Likely benign in CEP135 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-30). AlphaMissense: likely benign (0.0935); Rare (popmax 0.748%, afr); Associated with Inborn genetic diseases.

What condition is associated with CEP135 p.Met991Val (c.2971A>G)?

CEP135 p.Met991Val (c.2971A>G) is associated with Inborn genetic diseases, microcephaly 8, primary, autosomal recessive (ClinVar).

How common is CEP135 p.Met991Val (c.2971A>G) in the general population?

CEP135 p.Met991Val (c.2971A>G) is rare (popmax 0.748%, afr) (gnomAD).

What do computational predictors say about CEP135 p.Met991Val (c.2971A>G)?

AlphaMissense predicts likely benign (score 0.0935) — an in-silico prediction, not a clinical call.

CEP135 p.Met991Val

c.2971A>G · rs115646074 · VCV720572

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0935 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.748%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0935	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -4.52	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 5.1	GERP -2.5, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 72 kb · p 0.83 · regional, not allelic
Overall
CADD	15.01	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 0.748% African / African-American · 561/75,028 alleles

Filtering AF 0.696% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.676%

Overall 0.0392% 633/1,613,402 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.748%	134
Middle Eastern	0.108%	922
Remaining individualsnot grpmax-eligible	0.056%	1,784
Admixed American	0.0367%	2,728
European (non-Finnish)	0.000763%	131,109

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.Met991Val
Coding: c.2971A>G
MANE Select: NM_025009
dbSNP: rs115646074
Type: single nucleotide variant
Location: chr4:56017816 (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

Also linked: microcephaly 8, primary, autosomal recessive

Similar variants

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.Leu578Ter 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-met991val (accessed [today's date]).

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