Is ARSH p.Ser214Asn (c.641G>A) pathogenic?

ARSH p.Ser214Asn (c.641G>A) is classified Benign in ARSH (ClinVar, Single submitter, 2 submitters). AlphaMissense: ambiguous (0.4752); Common (popmax 12.2%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ARSH p.Ser214Asn (c.641G>A)?

AlphaMissense predicts ambiguous (score 0.4752) — an in-silico prediction, not a clinical call.

ARSH p.Ser214Asn

Q: How common is ARSH p.Ser214Asn (c.641G>A) in the general population?

ARSH p.Ser214Asn (c.641G>A) is common (popmax 12.2%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.641G>A · rs61995728 · VCV558983

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4752 · ACMG-weighted

gnomAD v4.1

Common

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

Computational evidence

Protein change
AlphaMissense	0.4752	ambiguous
REVEL	0.383	indeterminate
SaProt	LLR -6.22	tolerated
Splicing
SpliceAI	Δ0.65	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 1.6	GERP 0.78, phastCons 0.006
Regional constraint	o/e 0.97	unconstrained · MANE · 27 kb · p 0.56 · regional, not allelic
Overall
CADD	12.93	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 12.2% African / African-American · 6,949/56,912 alleles

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

Overall 0.681% 8,231/1,209,268 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	12.2%	8
Amishnot grpmax-eligible	2.04%	49
Admixed American	1.07%	94
Remaining individualsnot grpmax-eligible	0.998%	100
Middle Eastern	0.919%	109
European (non-Finnish)	0.028%	3,566
South Asian	0.0264%	3,781
Finnishnot grpmax-eligible	0.00215%	46,526

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.Ser214Asn
Coding: c.641G>A
MANE Select: NM_001011719
dbSNP: rs61995728
Type: single nucleotide variant
Location: chrX:3015270 (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-ser214asn (accessed [today's date]).

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