Is ARSH p.Arg414Met (c.1241G>T) pathogenic?

ARSH p.Arg414Met (c.1241G>T) is classified Uncertain significance in ARSH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-04). AlphaMissense: likely benign (0.1721); Ultra-rare (popmax 0.0118%, eas).

How common is ARSH p.Arg414Met (c.1241G>T) in the general population?

ARSH p.Arg414Met (c.1241G>T) is ultra-rare (popmax 0.0118%, eas) (gnomAD).

What do computational predictors say about ARSH p.Arg414Met (c.1241G>T)?

AlphaMissense predicts likely benign (score 0.1721) — an in-silico prediction, not a clinical call.

ARSH p.Arg414Met

c.1241G>T · rs766897149 · VCV3129901

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1721 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0118%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1721	likely benign
REVEL	0.387	indeterminate
SaProt	LLR -10.76	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.8	GERP -3.1
Regional constraint	o/e 0.97	unconstrained · MANE · 27 kb · p 0.56 · regional, not allelic
Overall
CADD	17.06	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 0.0118% East Asian · 4/33,763 alleles

Filtering AF 0.00396% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.000456% 5/1,097,628 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0118%	8,441
Remaining individualsnot grpmax-eligible	0.0021%	47,626

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.Arg414Met
Coding: c.1241G>T
MANE Select: NM_001011719
dbSNP: rs766897149
Type: single nucleotide variant
Location: chrX:3029288 (GRCh38)
Structure: AlphaFold pLDDT 94.15

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-arg414met (accessed [today's date]).

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