Is ASB8 p.Arg255Cys (c.763C>T) pathogenic?

ASB8 p.Arg255Cys (c.763C>T) is classified Uncertain significance in ASB8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: likely benign (0.2225); Very rare (popmax 0.00668%, eas).

How common is ASB8 p.Arg255Cys (c.763C>T) in the general population?

ASB8 p.Arg255Cys (c.763C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about ASB8 p.Arg255Cys (c.763C>T)?

AlphaMissense predicts likely benign (score 0.2225) — an in-silico prediction, not a clinical call.

ASB8 p.Arg255Cys

c.763C>T · rs747591267 · VCV2308335

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2225 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2225	likely benign
REVEL	0.686	pathogenic-leaning
SaProt	LLR -11.95	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 4,127 bp · p 0.00087 · regional, not allelic
Overall
CADD	32.0	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 0.00668% East Asian · 3/44,896 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00198% 32/1,614,000 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,965
South Asian	0.00439%	22,772
European (non-Finnish)	0.00195%	51,303
Finnishnot grpmax-eligible	0.00156%	64,036
African / African-American	0.00133%	74,916

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: ASB8
Protein: p.Arg255Cys
Coding: c.763C>T
MANE Select: NM_024095
dbSNP: rs747591267
Type: single nucleotide variant
Location: chr12:48149470 (GRCh38)
Gene constraint: LOEUF 1.004 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.41 · 5 PDB
Residue 255: the socs box domain

Full ASB8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ASB8 p.Ala125Glu Uncertain significance ★ ⚠ same type
ASB8 p.Ala142Thr Uncertain significance ★ ⚠ same type
ASB8 p.Ala175Thr Uncertain significance ★ ⚠ same type
ASB8 p.Ala254Thr Uncertain significance ★ ⚠ same type
ASB8 p.Ala278Pro Uncertain significance ★ ⚠ same type
ASB8 p.Arg135Gln Uncertain significance ★ ⚠ same type
ASB8 p.Arg190His Uncertain significance ★ ⚠ same type
ASB8 p.Arg21Cys 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/asb8-p-arg255cys (accessed [today's date]).

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