Is ARSL p.Ile565Ser (c.1694T>G) pathogenic?

ARSL p.Ile565Ser (c.1694T>G) is classified Conflicting classifications of pathogenicity in ARSL (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1208); Rare (popmax 0.34%, sas); Associated with chondrodysplasia punctata, brachytelephalangic, autosomal.

How common is ARSL p.Ile565Ser (c.1694T>G) in the general population?

ARSL p.Ile565Ser (c.1694T>G) is rare (popmax 0.34%, sas) (gnomAD).

What do computational predictors say about ARSL p.Ile565Ser (c.1694T>G)?

AlphaMissense predicts likely benign (score 0.1208) — an in-silico prediction, not a clinical call.

ARSL p.Ile565Ser

Q: What condition is associated with ARSL p.Ile565Ser (c.1694T>G)?

ARSL p.Ile565Ser (c.1694T>G) is associated with chondrodysplasia punctata, brachytelephalangic, autosomal, X-linked chondrodysplasia punctata 1 (ClinVar).

c.1694T>G · rs142375403 · VCV547861

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1208 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.34%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

chondrodysplasia punctata, brachytelephalangic, autosomal

Computational evidence

Protein change
AlphaMissense	0.1208	likely benign
REVEL	0.2	benign-leaning
SaProt	LLR -7.12	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 -4.8	GERP -2.7
Regional constraint	o/e 0.63	unconstrained · MANE · 26 kb · p 8.2e-17 · regional, not allelic
Overall
CADD	0.26	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 0.34% South Asian · 190/55,917 alleles

Filtering AF 0.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.285%

Overall 0.184% 2,208/1,202,578 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.34%	294
European (non-Finnish)	0.211%	473
Remaining individualsnot grpmax-eligible	0.173%	576
Middle Eastern	0.107%	932
Admixed American	0.0617%	1,621
African / African-American	0.0246%	4,069
Finnishnot grpmax-eligible	0.0151%	6,611

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.Ile565Ser
Coding: c.1694T>G
MANE Select: NM_000047
dbSNP: rs142375403
Type: single nucleotide variant
Location: chrX:2934908 (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-ile565ser (accessed [today's date]).

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