Is CEP76 p.Ser2Trp (c.5C>G) pathogenic?

CEP76 p.Ser2Trp (c.5C>G) is classified Uncertain significance in CEP76 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: ambiguous (0.5431); Very rare (popmax 0.000935%, nfe).

How common is CEP76 p.Ser2Trp (c.5C>G) in the general population?

CEP76 p.Ser2Trp (c.5C>G) is very rare (popmax 0.000935%, nfe) (gnomAD).

What do computational predictors say about CEP76 p.Ser2Trp (c.5C>G)?

AlphaMissense predicts ambiguous (score 0.5431) — an in-silico prediction, not a clinical call.

CEP76 p.Ser2Trp

c.5C>G · VCV4652551

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5431 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000935%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5431	ambiguous
REVEL	0.52	indeterminate
SaProt	LLR -10.25	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 29 kb · p 0.00019 · regional, not allelic
Overall
CADD	29.2	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 0.000935% European (non-Finnish) · 11/1,176,726 alleles

Filtering AF 0.000502% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000367%

Overall 0.000873% 14/1,602,986 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00484%	20,665
European (non-Finnish)grpmax	0.000935%	106,975

Remaining individuals 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: CEP76
Protein: p.Ser2Trp
Coding: c.5C>G
MANE Select: NM_024899
Type: single nucleotide variant
Location: chr18:12702544 (GRCh38)
Gene constraint: LOEUF 0.716 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.18

Full CEP76 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CEP76 p.Arg568Pro Likely pathogenic ★ same type
CEP76 p.Cys478Arg Likely pathogenic ★ same type
CEP76 p.Ile101Thr Likely pathogenic ★ ⚠ same type
CEP76 p.Leu166Pro Likely pathogenic ★ same type
CEP76 p.Lys374= Pathogenic ★ same type
CEP76 p.Pro103Ser Pathogenic ★ ⚠ same type
CEP76 p.Val24Asp Likely pathogenic ★ same type
CEP76 p.Val265Met Likely pathogenic ★ ⚠ 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/cep76-p-ser2trp (accessed [today's date]).

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