Is ARSH p.Arg358Cys (c.1072C>T) pathogenic?

ARSH p.Arg358Cys (c.1072C>T) is classified Benign in ARSH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2017-08-18). AlphaMissense: ambiguous (0.3921); Rare (popmax 0.363%, nfe).

How common is ARSH p.Arg358Cys (c.1072C>T) in the general population?

ARSH p.Arg358Cys (c.1072C>T) is rare (popmax 0.363%, nfe) (gnomAD).

What do computational predictors say about ARSH p.Arg358Cys (c.1072C>T)?

AlphaMissense predicts ambiguous (score 0.3921) — an in-silico prediction, not a clinical call.

ARSH p.Arg358Cys

c.1072C>T · rs146832237 · VCV558986

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3921 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.363%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3921	ambiguous
REVEL	0.802	moderately pathogenic-leaning
SaProt	LLR -13.26	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 0.46, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 27 kb · p 0.56 · regional, not allelic
Overall
CADD	21.4	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 0.363% European (non-Finnish) · 3,251/895,037 alleles

Filtering AF 0.353% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.349%

Overall 0.332% 4,016/1,209,331 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.16%	86
European (non-Finnish)grpmax	0.363%	275
Remaining individualsnot grpmax-eligible	0.246%	407
Middle Eastern	0.165%	604
Admixed American	0.0789%	1,268
South Asian	0.0635%	1,576
African / African-American	0.0438%	2,285
Ashkenazi Jewishnot grpmax-eligible	0.0136%	7,342

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg358Cys
Coding: c.1072C>T
MANE Select: NM_001011719
dbSNP: rs146832237
Type: single nucleotide variant
Location: chrX:3027348 (GRCh38)
Structure: AlphaFold pLDDT 94.15

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

Similar variants

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
ARSH p.Arg106His 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-arg358cys (accessed [today's date]).

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