Is ARSH p.Ala100Thr (c.298G>A) pathogenic?

ARSH p.Ala100Thr (c.298G>A) is classified Uncertain significance in ARSH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-10). AlphaMissense: ambiguous (0.3492); Very rare (popmax 0.00438%, amr).

How common is ARSH p.Ala100Thr (c.298G>A) in the general population?

ARSH p.Ala100Thr (c.298G>A) is very rare (popmax 0.00438%, amr) (gnomAD).

What do computational predictors say about ARSH p.Ala100Thr (c.298G>A)?

AlphaMissense predicts ambiguous (score 0.3492) — an in-silico prediction, not a clinical call.

ARSH p.Ala100Thr

c.298G>A · VCV3787521

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3492 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00438%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3492	ambiguous
REVEL	0.71	pathogenic-leaning
SaProt	LLR -11.36	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 5.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 27 kb · p 0.56 · regional, not allelic
Overall
CADD	20.6	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 0.00438% Admixed American · 2/45,640 alleles

Filtering AF 0.000726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000272%

Overall 0.000413% 5/1,209,355 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00438%	22,820
Remaining individualsnot grpmax-eligible	0.0021%	47,586
South Asian	0.00176%	56,712
European (non-Finnish)	0.000112%	894,975

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.Ala100Thr
Coding: c.298G>A
MANE Select: NM_001011719
Type: single nucleotide variant
Location: chrX:3013130 (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.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-ala100thr (accessed [today's date]).

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