Is ARSJ p.Val246Ile (c.736G>A) pathogenic?

ARSJ p.Val246Ile (c.736G>A) is classified Uncertain significance in ARSJ (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-01). AlphaMissense: likely benign (0.1337); Very rare (popmax 0.00415%, nfe).

How common is ARSJ p.Val246Ile (c.736G>A) in the general population?

ARSJ p.Val246Ile (c.736G>A) is very rare (popmax 0.00415%, nfe) (gnomAD).

What do computational predictors say about ARSJ p.Val246Ile (c.736G>A)?

AlphaMissense predicts likely benign (score 0.1337) — an in-silico prediction, not a clinical call.

ARSJ p.Val246Ile

c.736G>A · rs368878999 · VCV2471544

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1337 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00415%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1337	likely benign
REVEL	0.47	indeterminate
SaProt	LLR -7.98	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 5.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 77 kb · p 0.035 · regional, not allelic
Overall
CADD	24.3	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) · 49/1,180,028 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.0031% 50/1,614,004 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00415%	24,082
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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: ARSJ
Protein: p.Val246Ile
Coding: c.736G>A
MANE Select: NM_024590
dbSNP: rs368878999
Type: single nucleotide variant
Location: chr4:113903338 (GRCh38)
Gene constraint: LOEUF 0.951 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.34

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

Similar variants

ARSJ p.Ala107Thr Uncertain significance ★ ⚠ same type
ARSJ p.Ala295Ser Uncertain significance ★ ⚠ same type
ARSJ p.Ala444Pro Uncertain significance ★ ⚠ same type
ARSJ p.Ala7Glu Uncertain significance ★ ⚠ same type
ARSJ p.Arg283Gln Uncertain significance ★ ⚠ same type
ARSJ p.Arg283Leu Uncertain significance ★ ⚠ same type
ARSJ p.Arg479Pro Uncertain significance ★ ⚠ same type
ARSJ p.Arg511Lys Uncertain significance ★ ⚠ same type

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/arsj-p-val246ile (accessed [today's date]).

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