Is CEP76 p.Arg656His (c.1967G>A) pathogenic?

CEP76 p.Arg656His (c.1967G>A) is classified Uncertain significance in CEP76 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-11). AlphaMissense: ambiguous (0.3574); Very rare (popmax 0.00774%, nfe).

How common is CEP76 p.Arg656His (c.1967G>A) in the general population?

CEP76 p.Arg656His (c.1967G>A) is very rare (popmax 0.00774%, nfe) (gnomAD).

What do computational predictors say about CEP76 p.Arg656His (c.1967G>A)?

AlphaMissense predicts ambiguous (score 0.3574) — an in-silico prediction, not a clinical call.

CEP76 p.Arg656His

c.1967G>A · VCV3490914

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3574 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00774%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3574	ambiguous
REVEL	0.739	pathogenic-leaning
SaProt	LLR -5.64	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 29 kb · p 0.00019 · regional, not allelic
Overall
CADD	24.7	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 0.00774% European (non-Finnish) · 91/1,176,446 alleles

Filtering AF 0.00641% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00594%

Overall 0.00586% 94/1,603,620 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00774%	12,928
East Asian	0.00228%	43,898
Remaining individualsnot grpmax-eligible	0.00161%	62,024
African / African-American	0.00136%	73,778

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.Arg656His
Coding: c.1967G>A
MANE Select: NM_024899
Type: single nucleotide variant
Location: chr18:12673378 (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.Arg656Cys 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-arg656his (accessed [today's date]).

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