Is ARSI p.Arg261Trp (c.781C>T) pathogenic?

ARSI p.Arg261Trp (c.781C>T) is classified Uncertain significance in ARSI (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-25). AlphaMissense: likely pathogenic (0.5953); Ultra-rare (popmax 0.0132%, sas).

How common is ARSI p.Arg261Trp (c.781C>T) in the general population?

ARSI p.Arg261Trp (c.781C>T) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

What do computational predictors say about ARSI p.Arg261Trp (c.781C>T)?

AlphaMissense predicts likely pathogenic (score 0.5953) — an in-silico prediction, not a clinical call.

ARSI p.Arg261Trp

c.781C>T · VCV3949402

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5953 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5953	likely pathogenic
REVEL	0.898	moderately pathogenic-leaning
SaProt	LLR -14.34	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP -3.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 5,156 bp · p 0.021 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0132% South Asian · 12/91,078 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.00155% 25/1,613,790 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0132%	7,590
African / African-American	0.00133%	74,910
European (non-Finnish)	0.00102%	98,336

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: ARSI
Protein: p.Arg261Trp
Coding: c.781C>T
MANE Select: NM_001012301
Type: single nucleotide variant
Location: chr5:150298143 (GRCh38)
Gene constraint: LOEUF 1.403 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.35

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

Similar variants

ARSI p.Arg261Gln Uncertain significance ★★ ⚠ same residue
ARSI p.Ala216Thr Uncertain significance ★★ ⚠ same type
ARSI p.Ala259Val Uncertain significance ★★ ⚠ same type
ARSI p.Ala264Thr Uncertain significance ★★ ⚠ same type
ARSI p.Ala399Asp Uncertain significance ★★ ⚠ same type
ARSI p.Ala414Ser Uncertain significance ★★ ⚠ same type
ARSI p.Ala414Thr Uncertain significance ★★ ⚠ same type
ARSI p.Ala78Thr 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/arsi-p-arg261trp (accessed [today's date]).

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