Is ARSL p.Arg12Ser (c.36G>C) pathogenic?

ARSL p.Arg12Ser (c.36G>C) is classified Uncertain significance in ARSL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-01-25). AlphaMissense: likely benign (0.1831); Ultra-rare (popmax 0.0105%, nfe); Associated with chondrodysplasia punctata, brachytelephalangic, autosomal.

How common is ARSL p.Arg12Ser (c.36G>C) in the general population?

ARSL p.Arg12Ser (c.36G>C) is ultra-rare (popmax 0.0105%, nfe) (gnomAD).

What do computational predictors say about ARSL p.Arg12Ser (c.36G>C)?

AlphaMissense predicts likely benign (score 0.1831) — an in-silico prediction, not a clinical call.

ARSL p.Arg12Ser

Q: What condition is associated with ARSL p.Arg12Ser (c.36G>C)?

ARSL p.Arg12Ser (c.36G>C) is associated with chondrodysplasia punctata, brachytelephalangic, autosomal, X-linked chondrodysplasia punctata 1 (ClinVar).

c.36G>C · rs122460151 · VCV11522

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1831 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0105%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

chondrodysplasia punctata, brachytelephalangic, autosomal

Computational evidence

Protein change
AlphaMissense	0.1831	likely benign
REVEL	0.596	indeterminate
SaProt	LLR -5.39	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.65	acceptor gain · deltas
Pangolin	Δ0.59	gain · loss 0.19 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.2	GERP 1.1, phastCons 0.98
Regional constraint	o/e 0.63	unconstrained · MANE · 26 kb · p 8.2e-17 · regional, not allelic
Overall
CADD	17.32	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 0.0105% European (non-Finnish) · 94/895,396 alleles

Filtering AF 0.00875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00812%

Overall 0.00826% 100/1,210,446 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0107%	9,333
European (non-Finnish)grpmax	0.0105%	9,526
Remaining individualsnot grpmax-eligible	0.0021%	47,605

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ARSL
Protein: p.Arg12Ser
Coding: c.36G>C
MANE Select: NM_000047
dbSNP: rs122460151
Type: single nucleotide variant
Location: chrX:2958423 (GRCh38)
Structure: AlphaFold pLDDT 92.57
Residue 12: a UniProt-annotated variant site (in cdpx1; no effect on arylsulfatase activity, protein stability and localization to the golgi apparatus)

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

Disease context

chondrodysplasia punctata, brachytelephalangic, autosomal — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: X-linked chondrodysplasia punctata 1

Similar variants

ARSL c.1289+1G>A Pathogenic/Likely pathogenic ★★ same condition
ARSL c.24-2A>G Likely pathogenic ★★ same condition
ARSL p.Gly117Arg Pathogenic/Likely pathogenic ★★ same condition
ARSL p.Gly73Ser Likely pathogenic ★★ ⚠ same condition
ARSL p.Ala182Thr Uncertain significance ★★ ⚠ same condition
ARSL p.Ala251Val Uncertain significance ★★ ⚠ same condition
ARSL p.Ala45Val Uncertain significance ★★ ⚠ same condition
ARSL p.Arg190His Uncertain significance ★★ ⚠ same condition

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/arsl-p-arg12ser (accessed [today's date]).

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