Is ARSH p.Arg66Trp (c.196C>T) pathogenic?

ARSH p.Arg66Trp (c.196C>T) is classified Conflicting classifications of pathogenicity in ARSH (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-03-01). AlphaMissense: ambiguous (0.4732); Ultra-rare (popmax 0.069%, mid).

How common is ARSH p.Arg66Trp (c.196C>T) in the general population?

ARSH p.Arg66Trp (c.196C>T) is ultra-rare (popmax 0.069%, mid) (gnomAD).

What do computational predictors say about ARSH p.Arg66Trp (c.196C>T)?

AlphaMissense predicts ambiguous (score 0.4732) — an in-silico prediction, not a clinical call.

ARSH p.Arg66Trp

c.196C>T · rs148749736 · VCV2362277

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4732 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.069%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4732	ambiguous
REVEL	0.816	moderately pathogenic-leaning
SaProt	LLR -14.28	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -7.1	GERP -1.8
Regional constraint	o/e 0.97	unconstrained · MANE · 27 kb · p 0.56 · regional, not allelic
Overall
CADD	21.9	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 0.069% Middle Eastern · 3/4,349 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.017%

Overall 0.0171% 207/1,209,371 alleles · ultra-rare exomes 196/1,097,555 · genomes 11/111,816 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.069%	1,450
European (non-Finnish)	0.0203%	4,917
Remaining individualsnot grpmax-eligible	0.0189%	5,288
East Asian	0.0148%	6,752
Ashkenazi Jewishnot grpmax-eligible	0.00454%	22,020
Admixed American	0.00438%	22,816
South Asian	0.00353%	28,329
African / African-American	0.00349%	28,623
Finnishnot grpmax-eligible	0.00215%	46,521

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.Arg66Trp
Coding: c.196C>T
MANE Select: NM_001011719
dbSNP: rs148749736
Type: single nucleotide variant
Location: chrX:3010133 (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-arg66trp (accessed [today's date]).

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