Is ARSF p.Arg249Trp (c.745C>T) pathogenic?

ARSF p.Arg249Trp (c.745C>T) is classified Uncertain significance in ARSF (ClinVar, Single submitter, 2 submitters; last evaluated 2022-10-03). AlphaMissense: ambiguous (0.4436); Ultra-rare (popmax 0.0385%, eas).

How common is ARSF p.Arg249Trp (c.745C>T) in the general population?

ARSF p.Arg249Trp (c.745C>T) is ultra-rare (popmax 0.0385%, eas) (gnomAD).

What do computational predictors say about ARSF p.Arg249Trp (c.745C>T)?

AlphaMissense predicts ambiguous (score 0.4436) — an in-silico prediction, not a clinical call.

ARSF p.Arg249Trp

c.745C>T · rs749415338 · VCV2406593

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4436 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0385%, eas)

Computational evidence

Protein change
AlphaMissense	0.4436	ambiguous
REVEL	0.555	indeterminate
SaProt	LLR -13.03	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.2	GERP -3.4
Regional constraint	o/e 1.04	unconstrained · MANE · 44 kb · p 0.34 · regional, not allelic
Overall
CADD	15.66	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 0.0385% East Asian · 13/33,739 alleles

Filtering AF 0.0228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.018%

Overall 0.00149% 18/1,208,583 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0385%	2,595
Remaining individualsnot grpmax-eligible	0.0021%	47,530
European (non-Finnish)	0.000447%	223,648

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: ARSF
Protein: p.Arg249Trp
Coding: c.745C>T
MANE Select: NM_001201539
dbSNP: rs749415338
Type: single nucleotide variant
Location: chrX:3084581 (GRCh38)
Structure: AlphaFold pLDDT 90.98

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

Similar variants

ARSF p.Arg249Leu Uncertain significance ★ ⚠ same residue
ARSF c.1102+5G>A Likely benign ★★ same type
ARSF p.Pro6= Benign ★★ same type
ARSF p.Ala112Ser Uncertain significance ★ ⚠ same type
ARSF p.Ala411Pro Uncertain significance ★ ⚠ same type
ARSF p.Ala411Thr Uncertain significance ★ ⚠ same type
ARSF p.Ala84Pro Uncertain significance ★ ⚠ same type
ARSF p.Arg103Cys 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/arsf-p-arg249trp (accessed [today's date]).

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