Is ARSH p.Cys129= (c.387T>C) pathogenic?

ARSH p.Cys129= (c.387T>C) is classified Benign in ARSH (ClinVar, Single submitter, 2 submitters). Common (popmax 12.2%, afr) — too common for a highly-penetrant pathogenic allele.

ARSH p.Cys129=

Q: How common is ARSH p.Cys129= (c.387T>C) in the general population?

ARSH p.Cys129= (c.387T>C) is common (popmax 12.2%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.387T>C · rs143359225 · VCV558979

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 12.2%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.1	GERP -2.2
Overall
CADD	1.226	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12.2% African / African-American · 6,980/57,048 alleles

Filtering AF 12% ClinGen BA1/BS1 input FAF95, joint · FAF99 11.9%

Overall 0.684% 8,280/1,209,716 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	12.2%	8
Amishnot grpmax-eligible	2.05%	49
Admixed American	1.06%	94
Remaining individualsnot grpmax-eligible	1.03%	97
Middle Eastern	0.924%	108
South Asian	0.0317%	3,153
European (non-Finnish)	0.0283%	3,538
Finnishnot grpmax-eligible	0.00214%	46,626

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.Cys129=
Coding: c.387T>C
MANE Select: NM_001011719
dbSNP: rs143359225
Type: single nucleotide variant
Location: chrX:3015016 (GRCh38)
Structure: AlphaFold pLDDT 94.15

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

Similar variants

ARSH p.Cys129Arg Uncertain significance ★ ⚠ same residue
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

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-cys129 (accessed [today's date]).

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