Is ASB8 p.Ala175Thr (c.523G>A) pathogenic?

ASB8 p.Ala175Thr (c.523G>A) is classified Uncertain significance in ASB8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-20). AlphaMissense: likely pathogenic (0.6567); Very rare (popmax 0.0011%, sas).

How common is ASB8 p.Ala175Thr (c.523G>A) in the general population?

ASB8 p.Ala175Thr (c.523G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ASB8 p.Ala175Thr (c.523G>A)?

AlphaMissense predicts likely pathogenic (score 0.6567) — an in-silico prediction, not a clinical call.

ASB8 p.Ala175Thr

c.523G>A · VCV3951530

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6567 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6567	likely pathogenic
REVEL	0.689	pathogenic-leaning
SaProt	LLR -13.59	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 4,127 bp · p 0.00087 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0011% South Asian · 1/91,072 alleles

Overall 0.000137% 2/1,461,784 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,072
European (non-Finnish)	8.47e-05%	1,179,956

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.Ala175Thr
Coding: c.523G>A
MANE Select: NM_024095
Type: single nucleotide variant
Location: chr12:48149710 (GRCh38)
Gene constraint: LOEUF 1.004 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.41 · 5 PDB

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.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
ASB8 p.Arg21Gly 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-ala175thr (accessed [today's date]).

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