Is ARSL p.Ala422Val (c.1265C>T) pathogenic?

ARSL p.Ala422Val (c.1265C>T) is classified Conflicting classifications of pathogenicity in ARSL (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-11). AlphaMissense: likely benign (0.1999); Ultra-rare (popmax 0.0122%, afr); Associated with chondrodysplasia punctata, brachytelephalangic, autosomal.

How common is ARSL p.Ala422Val (c.1265C>T) in the general population?

ARSL p.Ala422Val (c.1265C>T) is ultra-rare (popmax 0.0122%, afr) (gnomAD).

What do computational predictors say about ARSL p.Ala422Val (c.1265C>T)?

AlphaMissense predicts likely benign (score 0.1999) — an in-silico prediction, not a clinical call.

ARSL p.Ala422Val

Q: What condition is associated with ARSL p.Ala422Val (c.1265C>T)?

ARSL p.Ala422Val (c.1265C>T) is associated with chondrodysplasia punctata, brachytelephalangic, autosomal, X-linked chondrodysplasia punctata 1 (ClinVar).

c.1265C>T · rs758398497 · VCV2439211

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1999 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

chondrodysplasia punctata, brachytelephalangic, autosomal

Computational evidence

Protein change
AlphaMissense	0.1999	likely benign
REVEL	0.411	indeterminate
SaProt	LLR -9.90	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 -2.5	GERP -2.8
Regional constraint	o/e 0.63	unconstrained · MANE · 26 kb · p 8.2e-17 · regional, not allelic
Overall
CADD	1.698	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 0.0122% African / African-American · 7/57,327 alleles

Filtering AF 0.00566% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00405%

Overall 0.00297% 36/1,210,129 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0122%	8,190
Admixed American	0.0109%	9,162
South Asian	0.00352%	28,414
East Asian	0.00296%	33,735
European (non-Finnish)	0.00223%	44,761
Remaining individualsnot grpmax-eligible	0.0021%	47,588

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.Ala422Val
Coding: c.1265C>T
MANE Select: NM_000047
dbSNP: rs758398497
Type: single nucleotide variant
Location: chrX:2938119 (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 p.Ala422Thr Uncertain significance ★ ⚠ same residue
ARSL p.Ala422= Likely benign ★ same residue
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

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-ala422val (accessed [today's date]).

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