Is ASL p.Arg168Ser (c.502C>A) pathogenic?

ASL p.Arg168Ser (c.502C>A) is classified Likely pathogenic in ASL (ClinVar, Single submitter, 1 submitter; last evaluated 2020-10-01). AlphaMissense: likely pathogenic (0.8697); Very rare (popmax 0.000254%, nfe); Associated with neurodevelopmental disorder.

What condition is associated with ASL p.Arg168Ser (c.502C>A)?

ASL p.Arg168Ser (c.502C>A) is associated with neurodevelopmental disorder (ClinVar).

How common is ASL p.Arg168Ser (c.502C>A) in the general population?

ASL p.Arg168Ser (c.502C>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about ASL p.Arg168Ser (c.502C>A)?

AlphaMissense predicts likely pathogenic (score 0.8697) — an in-silico prediction, not a clinical call.

ASL p.Arg168Ser

c.502C>A · rs766832061 · VCV1064860

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8697 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.8697	likely pathogenic ✓ concordant with ClinVar
REVEL	0.77	pathogenic-leaning
SaProt	LLR -10.42	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 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 17 kb · p 0.00078 · regional, not allelic
Overall
CADD	26.6	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 0.000254% European (non-Finnish) · 3/1,180,022 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,614 alleles · very rare

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: ASL
Protein: p.Arg168Ser
Coding: c.502C>A
MANE Select: NM_000048
dbSNP: rs766832061
Type: single nucleotide variant
Location: chr7:66086640 (GRCh38)
Gene constraint: LOEUF 0.937 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.51 · 2 PDB
Residue 168: a UniProt-annotated variant site (in arginsa); a β-strand

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

Disease context

neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ASL p.Arg168Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
ASL p.Arg168His Conflicting classifications of pathogenicity ★ ⚠ same residue
ASL p.Arg168fs Likely pathogenic ★ same residue
ASL p.Met125Thr Likely pathogenic ★ ⚠ same condition
ASL p.Val349fs Pathogenic ★★ same condition
ASL c.1062+5G>C Likely pathogenic ★★ same type
ASL c.1143+1G>T Pathogenic/Likely pathogenic ★★ same type
ASL c.13-1G>C Pathogenic/Likely pathogenic ★★ 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/asl-p-arg168ser (accessed [today's date]).

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