Is ASB18 p.Pro421Leu (c.1262C>T) pathogenic?

ASB18 p.Pro421Leu (c.1262C>T) is classified Uncertain significance in ASB18 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely benign (0.2812); Very rare (popmax 0.00266%, afr).

How common is ASB18 p.Pro421Leu (c.1262C>T) in the general population?

ASB18 p.Pro421Leu (c.1262C>T) is very rare (popmax 0.00266%, afr) (gnomAD).

What do computational predictors say about ASB18 p.Pro421Leu (c.1262C>T)?

AlphaMissense predicts likely benign (score 0.2812) — an in-silico prediction, not a clinical call.

ASB18 p.Pro421Leu

c.1262C>T · VCV4152400

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2812 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00266%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2812	likely benign
REVEL	0.303	indeterminate
SaProt	LLR -13.07	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.47, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 69 kb · p 0.13 · regional, not allelic
Overall
CADD	23.2	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 0.00266% African / African-American · 2/75,054 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,613,752 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00266%	37,527
Admixed American	0.00167%	60,004
European (non-Finnish)	8.48e-05%	1,179,837

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: ASB18
Protein: p.Pro421Leu
Coding: c.1262C>T
MANE Select: NM_212556
Type: single nucleotide variant
Location: chr2:236195011 (GRCh38)
Gene constraint: LOEUF 1.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.50
Residue 421: the socs box domain

Full ASB18 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ASB18 p.Ala127Thr Uncertain significance ★ ⚠ same type
ASB18 p.Ala134Thr Uncertain significance ★ ⚠ same type
ASB18 p.Ala166Pro Uncertain significance ★ ⚠ same type
ASB18 p.Ala187Glu Uncertain significance ★ ⚠ same type
ASB18 p.Ala196Thr Uncertain significance ★ ⚠ same type
ASB18 p.Ala288Gly Uncertain significance ★ ⚠ same type
ASB18 p.Ala317Thr Uncertain significance ★ ⚠ same type
ASB18 p.Ala321Gly 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/asb18-p-pro421leu (accessed [today's date]).

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