Is CEP76 p.Ser221Ala (c.661T>G) pathogenic?

CEP76 p.Ser221Ala (c.661T>G) is classified Uncertain significance in CEP76 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). AlphaMissense: likely benign (0.0621); Very rare (popmax 0.00356%, nfe).

How common is CEP76 p.Ser221Ala (c.661T>G) in the general population?

CEP76 p.Ser221Ala (c.661T>G) is very rare (popmax 0.00356%, nfe) (gnomAD).

What do computational predictors say about CEP76 p.Ser221Ala (c.661T>G)?

AlphaMissense predicts likely benign (score 0.0621) — an in-silico prediction, not a clinical call.

CEP76 p.Ser221Ala

c.661T>G · VCV4652548

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0621 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0621	likely benign
REVEL	0.204	benign-leaning
SaProt	LLR -6.17	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 9.1	GERP 1.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 29 kb · p 0.00019 · regional, not allelic
Overall
CADD	20.2	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 0.00356% European (non-Finnish) · 42/1,179,838 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00285% 46/1,613,614 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00356%	28,091
Admixed American	0.00334%	29,962
Remaining individualsnot grpmax-eligible	0.0032%	31,227

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.Ser221Ala
Coding: c.661T>G
MANE Select: NM_024899
Type: single nucleotide variant
Location: chr18:12697268 (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.Ser221Leu Uncertain significance ★ ⚠ same residue
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

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-ser221ala (accessed [today's date]).

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