Is ARSL p.Ile348Thr (c.1043T>C) pathogenic?

ARSL p.Ile348Thr (c.1043T>C) is classified Conflicting classifications of pathogenicity in ARSL (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-10-22). AlphaMissense: likely benign (0.1375); Ultra-rare (popmax 0.0388%, sas); Associated with chondrodysplasia punctata, brachytelephalangic, autosomal.

What condition is associated with ARSL p.Ile348Thr (c.1043T>C)?

ARSL p.Ile348Thr (c.1043T>C) is associated with chondrodysplasia punctata, brachytelephalangic, autosomal (ClinVar).

How common is ARSL p.Ile348Thr (c.1043T>C) in the general population?

ARSL p.Ile348Thr (c.1043T>C) is ultra-rare (popmax 0.0388%, sas) (gnomAD).

What do computational predictors say about ARSL p.Ile348Thr (c.1043T>C)?

AlphaMissense predicts likely benign (score 0.1375) — an in-silico prediction, not a clinical call.

ARSL p.Ile348Thr

c.1043T>C · rs759330790 · VCV2521822

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1375 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0388%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

chondrodysplasia punctata, brachytelephalangic, autosomal

Computational evidence

Protein change
AlphaMissense	0.1375	likely benign
REVEL	0.368	indeterminate
SaProt	LLR -9.39	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP 0.47, phastCons 0.12
Regional constraint	o/e 0.63	unconstrained · MANE · 26 kb · p 8.2e-17 · regional, not allelic
Overall
CADD	9.973	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 0.0388% South Asian · 22/56,714 alleles

Filtering AF 0.0262% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.00571% 69/1,209,301 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0388%	2,578
Remaining individualsnot grpmax-eligible	0.00631%	15,852
European (non-Finnish)	0.00469%	21,312
African / African-American	0.0035%	28,534

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.Ile348Thr
Coding: c.1043T>C
MANE Select: NM_000047
dbSNP: rs759330790
Type: single nucleotide variant
Location: chrX:2943148 (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

Similar variants

ARSL c.24-2A>G 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
ARSL p.Arg190His Uncertain significance ★★ ⚠ same condition
ARSL p.Asp413Glu 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-ile348thr (accessed [today's date]).

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