Is ASB5 p.Leu220Phe (c.658C>T) pathogenic?

ASB5 p.Leu220Phe (c.658C>T) is classified Uncertain significance in ASB5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-02). AlphaMissense: likely pathogenic (0.5768); Very rare (popmax 0.00288%, nfe).

How common is ASB5 p.Leu220Phe (c.658C>T) in the general population?

ASB5 p.Leu220Phe (c.658C>T) is very rare (popmax 0.00288%, nfe) (gnomAD).

What do computational predictors say about ASB5 p.Leu220Phe (c.658C>T)?

AlphaMissense predicts likely pathogenic (score 0.5768) — an in-silico prediction, not a clinical call.

ASB5 p.Leu220Phe

c.658C>T · rs757419854 · VCV3130192

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5768 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00288%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5768	likely pathogenic
REVEL	0.754	pathogenic-leaning
SaProt	LLR -12.93	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.23	donor loss, 12 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 54 kb · p 0.91 · regional, not allelic
Overall
CADD	28.3	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 0.00288% European (non-Finnish) · 34/1,179,684 alleles

Filtering AF 0.00207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00223% 36/1,612,802 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00288%	34,697
Remaining individualsnot grpmax-eligible	0.0016%	62,434
African / African-American	0.00134%	74,848

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: ASB5
Protein: p.Leu220Phe
Coding: c.658C>T
MANE Select: NM_080874
dbSNP: rs757419854
Type: single nucleotide variant
Location: chr4:176221167 (GRCh38)
Gene constraint: LOEUF 1.317 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.93

Full ASB5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ASB5 p.Ala175Thr Uncertain significance ★ ⚠ same type
ASB5 p.Ala176Ser Uncertain significance ★ ⚠ same type
ASB5 p.Ala51Pro Uncertain significance ★ ⚠ same type
ASB5 p.Ala69Val Uncertain significance ★ ⚠ same type
ASB5 p.Ala77Ser Uncertain significance ★ ⚠ same type
ASB5 p.Ala85Thr Uncertain significance ★ ⚠ same type
ASB5 p.Arg302Gln Uncertain significance ★ ⚠ same type
ASB5 p.Asn142Lys 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/asb5-p-leu220phe (accessed [today's date]).

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