Is ARSH p.Lys115Arg (c.344A>G) pathogenic?

ARSH p.Lys115Arg (c.344A>G) is classified Uncertain significance in ARSH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-12). AlphaMissense: likely benign (0.2469); Ultra-rare (popmax 0.0445%, sas).

How common is ARSH p.Lys115Arg (c.344A>G) in the general population?

ARSH p.Lys115Arg (c.344A>G) is ultra-rare (popmax 0.0445%, sas) (gnomAD).

What do computational predictors say about ARSH p.Lys115Arg (c.344A>G)?

AlphaMissense predicts likely benign (score 0.2469) — an in-silico prediction, not a clinical call.

ARSH p.Lys115Arg

c.344A>G · VCV3787548

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2469 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0445%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2469	likely benign
REVEL	0.759	pathogenic-leaning
SaProt	LLR -12.53	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	Δ0.32	acceptor gain · deltas
Pangolin	Δ0.21	gain · loss 0.08 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 8.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 27 kb · p 0.56 · regional, not allelic
Overall
CADD	22.8	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 0.0445% South Asian · 25/56,152 alleles

Filtering AF 0.0309% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0264%

Overall 0.00238% 26/1,093,270 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0445%	2,246
Remaining individualsnot grpmax-eligible	0.00211%	47,378

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: ARSH
Protein: p.Lys115Arg
Coding: c.344A>G
MANE Select: NM_001011719
Type: single nucleotide variant
Location: chrX:3014973 (GRCh38)
Structure: AlphaFold pLDDT 94.15
Residue 115: a binding site

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

Similar variants

ARSH p.Arg358Cys Benign ★★ ⚠ same type
ARSH p.Arg37His Benign ★★ ⚠ same type
ARSH p.Met408Ile Benign ★★ same type
ARSH p.Pro144Thr Benign ★★ ⚠ same type
ARSH p.Ala100Thr Uncertain significance ★ ⚠ same type
ARSH p.Ala14Thr Uncertain significance ★ ⚠ same type
ARSH p.Ala175Val Uncertain significance ★ ⚠ same type
ARSH p.Ala187Thr 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/arsh-p-lys115arg (accessed [today's date]).

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