Is ARSL p.Cys8Ser (c.23G>C) pathogenic?

ARSL p.Cys8Ser (c.23G>C) is classified Uncertain significance in ARSL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-06-20). AlphaMissense: likely benign (0.079); Very rare (popmax 0.00415%, nfe); Associated with chondrodysplasia punctata, brachytelephalangic, autosomal.

How common is ARSL p.Cys8Ser (c.23G>C) in the general population?

ARSL p.Cys8Ser (c.23G>C) is very rare (popmax 0.00415%, nfe) (gnomAD).

What do computational predictors say about ARSL p.Cys8Ser (c.23G>C)?

AlphaMissense predicts likely benign (score 0.079) — an in-silico prediction, not a clinical call.

ARSL p.Cys8Ser

Q: What condition is associated with ARSL p.Cys8Ser (c.23G>C)?

ARSL p.Cys8Ser (c.23G>C) is associated with chondrodysplasia punctata, brachytelephalangic, autosomal, X-linked chondrodysplasia punctata 1 (ClinVar).

c.23G>C · rs1057521599 · VCV383365

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.079 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00415%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

chondrodysplasia punctata, brachytelephalangic, autosomal

Computational evidence

Protein change
AlphaMissense	0.079	likely benign
REVEL	0.389	indeterminate
SaProt	LLR -5.07	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.74	acceptor loss · deltas
Pangolin	Δ0.61	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.3	GERP 0.58, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 26 kb · p 8.2e-17 · regional, not allelic
Overall
CADD	18.97	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 0.00415% European (non-Finnish) · 36/868,220 alleles

Filtering AF 0.00303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00269%

Overall 0.00324% 38/1,173,549 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00415%	24,117
East Asian	0.003%	33,288
Remaining individualsnot grpmax-eligible	0.00216%	46,393

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.Cys8Ser
Coding: c.23G>C
MANE Select: NM_000047
dbSNP: rs1057521599
Type: single nucleotide variant
Location: chrX:2960378 (GRCh38)
Structure: AlphaFold pLDDT 92.57

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.Arg12Ser 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-cys8ser (accessed [today's date]).

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