Is ARSH p.Pro537Leu (c.1610C>T) pathogenic?

ARSH p.Pro537Leu (c.1610C>T) is classified Conflicting classifications of pathogenicity in ARSH (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-23). AlphaMissense: likely benign (0.3199); Ultra-rare (popmax 0.0716%, nfe).

How common is ARSH p.Pro537Leu (c.1610C>T) in the general population?

ARSH p.Pro537Leu (c.1610C>T) is ultra-rare (popmax 0.0716%, nfe) (gnomAD).

What do computational predictors say about ARSH p.Pro537Leu (c.1610C>T)?

AlphaMissense predicts likely benign (score 0.3199) — an in-silico prediction, not a clinical call.

ARSH p.Pro537Leu

c.1610C>T · rs138812517 · VCV2659866

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3199 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0716%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3199	likely benign
REVEL	0.649	pathogenic-leaning
SaProt	LLR -10.06	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP 1.2, phastCons 0.13
Regional constraint	o/e 0.97	unconstrained · MANE · 27 kb · p 0.56 · regional, not allelic
Overall
CADD	21.5	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 0.0716% European (non-Finnish) · 641/894,631 alleles

Filtering AF 0.067% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0652%

Overall 0.0556% 672/1,208,973 alleles · ultra-rare exomes 641/1,096,853 · genomes 31/112,120 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0716%	1,396
Remaining individualsnot grpmax-eligible	0.0504%	1,983
African / African-American	0.0105%	9,557
Ashkenazi Jewishnot grpmax-eligible	0.00454%	22,018

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.Pro537Leu
Coding: c.1610C>T
MANE Select: NM_001011719
dbSNP: rs138812517
Type: single nucleotide variant
Location: chrX:3033306 (GRCh38)
Structure: AlphaFold pLDDT 94.15

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

Similar variants

ARSH p.Pro537= Likely benign ★ 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-pro537leu (accessed [today's date]).

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