Is ARSL p.Thr481Met (c.1442C>T) pathogenic?

ARSL p.Thr481Met (c.1442C>T) is classified Conflicting classifications of pathogenicity in ARSL (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-24). AlphaMissense: likely benign (0.2678); Very rare (popmax 0.000223%, nfe); Associated with X-linked chondrodysplasia punctata 1.

What condition is associated with ARSL p.Thr481Met (c.1442C>T)?

ARSL p.Thr481Met (c.1442C>T) is associated with X-linked chondrodysplasia punctata 1 (ClinVar).

How common is ARSL p.Thr481Met (c.1442C>T) in the general population?

ARSL p.Thr481Met (c.1442C>T) is very rare (popmax 0.000223%, nfe) (gnomAD).

What do computational predictors say about ARSL p.Thr481Met (c.1442C>T)?

AlphaMissense predicts likely benign (score 0.2678) — an in-silico prediction, not a clinical call.

ARSL p.Thr481Met

c.1442C>T · rs80338713 · VCV21032

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2678 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000223%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked chondrodysplasia punctata 1

Computational evidence

Protein change
AlphaMissense	0.2678	likely benign
REVEL	0.656	pathogenic-leaning
SaProt	LLR -12.57	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 0.25, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 26 kb · p 8.2e-17 · regional, not allelic
Overall
CADD	21.5	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 0.000223% European (non-Finnish) · 2/895,344 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000182% 2/1,097,776 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: ARSL
Protein: p.Thr481Met
Coding: c.1442C>T
MANE Select: NM_000047
dbSNP: rs80338713
Type: single nucleotide variant
Location: chrX:2935160 (GRCh38)
Structure: AlphaFold pLDDT 92.57
Residue 481: a UniProt-annotated variant site (in cdpx1)

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

Disease context

X-linked chondrodysplasia punctata 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ARSL p.Thr481= Likely benign ★ same residue
ARSL c.1289+1G>A Pathogenic/Likely pathogenic ★★ same condition
ARSL p.Gly117Arg Pathogenic/Likely pathogenic ★★ same condition
ARSL p.Gly73Ser Likely pathogenic ★★ ⚠ same condition
ARSL p.Arg12Ser Uncertain significance ★★ ⚠ same condition
ARSL p.Asp413Glu Uncertain significance ★★ ⚠ same condition
ARSL p.Cys8Ser Uncertain significance ★★ ⚠ same condition
ARSL p.Pro38Leu 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-thr481met (accessed [today's date]).

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