Is ARSD p.Ala539Asp (c.1616C>A) pathogenic?

ARSD p.Ala539Asp (c.1616C>A) is classified Uncertain significance in ARSD (ClinVar, Single submitter, 2 submitters; last evaluated 2025-05-26). AlphaMissense: likely benign (0.0861); Rare (popmax 0.157%, eas).

How common is ARSD p.Ala539Asp (c.1616C>A) in the general population?

ARSD p.Ala539Asp (c.1616C>A) is rare (popmax 0.157%, eas) (gnomAD).

What do computational predictors say about ARSD p.Ala539Asp (c.1616C>A)?

AlphaMissense predicts likely benign (score 0.0861) — an in-silico prediction, not a clinical call.

ARSD p.Ala539Asp

c.1616C>A · rs201828808 · VCV2458188

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0861 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.157%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0861	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -5.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.2	GERP -2.2
Regional constraint	o/e 0.90	unconstrained · MANE · 2,698 bp · p 0.17 · regional, not allelic
Overall
CADD	10.01	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.157% East Asian · 53/33,735 alleles

Filtering AF 0.123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.111%

Overall 0.00661% 80/1,210,336 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.157%	637
South Asian	0.0353%	2,834
Remaining individualsnot grpmax-eligible	0.0126%	7,933
European (non-Finnish)	0.000112%	895,151

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: ARSD
Protein: p.Ala539Asp
Coding: c.1616C>A
MANE Select: NM_001669
dbSNP: rs201828808
Type: single nucleotide variant
Location: chrX:2907437 (GRCh38)
Structure: AlphaFold pLDDT 92.71

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

Similar variants

ARSD p.Ala539Thr Uncertain significance ★ ⚠ same residue
ARSD p.Cys577= Benign ★★ same type
ARSD p.Gly323= Likely benign ★★ same type
ARSD p.Gly409Glu Benign ★★ same type
ARSD p.Ser224Cys Benign ★★ ⚠ same type
ARSD p.Val500Ile Benign ★★ same type
ARSD p.Ala109Thr Uncertain significance ★ ⚠ same type
ARSD p.Ala14Thr 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/arsd-p-ala539asp (accessed [today's date]).

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