Is CLYBL p.Arg4Cys (c.10C>T) pathogenic?

CLYBL p.Arg4Cys (c.10C>T) is classified Uncertain significance in CLYBL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-06). AlphaMissense: likely pathogenic (0.5956); Ultra-rare (popmax 0.0222%, mid).

How common is CLYBL p.Arg4Cys (c.10C>T) in the general population?

CLYBL p.Arg4Cys (c.10C>T) is ultra-rare (popmax 0.0222%, mid) (gnomAD).

What do computational predictors say about CLYBL p.Arg4Cys (c.10C>T)?

AlphaMissense predicts likely pathogenic (score 0.5956) — an in-silico prediction, not a clinical call.

CLYBL p.Arg4Cys

c.10C>T · rs865840508 · VCV2481971

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5956 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0222%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5956	likely pathogenic
REVEL	0.025	moderately benign-leaning
SaProt	LLR -6.95	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.5	GERP -3
Regional constraint	o/e 1.05	unconstrained · MANE · 285 kb · p 0.27 · regional, not allelic
Overall
CADD	19.32	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 0.0222% Middle Eastern · 1/4,502 alleles

Filtering AF 0.000568% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000448%

Overall 0.00121% 18/1,492,428 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0222%	4,502
African / African-American	0.00292%	34,298
East Asian	0.00286%	35,002
South Asian	0.00254%	39,334
European (non-Finnish)	0.00106%	93,959

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: CLYBL
Protein: p.Arg4Cys
Coding: c.10C>T
MANE Select: NM_206808
dbSNP: rs865840508
Type: single nucleotide variant
Location: chr13:99606705 (GRCh38)
Gene constraint: LOEUF 1.186 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.00 · 3 PDB

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

Similar variants

CLYBL p.Arg4Ser Uncertain significance ★ ⚠ same residue
CLYBL p.Ala116Val Uncertain significance ★ ⚠ same type
CLYBL p.Ala13Asp Uncertain significance ★ ⚠ same type
CLYBL p.Ala13Val Uncertain significance ★ ⚠ same type
CLYBL p.Ala16Val Uncertain significance ★ ⚠ same type
CLYBL p.Ala17Ser Uncertain significance ★ ⚠ same type
CLYBL p.Ala17Thr Uncertain significance ★ ⚠ same type
CLYBL p.Ala17Val Uncertain significance ★ ⚠ 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/clybl-p-arg4cys (accessed [today's date]).

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