Is IDS p.Arg445Ser (c.1333C>A) pathogenic?

IDS p.Arg445Ser (c.1333C>A) is classified Uncertain significance in IDS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-20). AlphaMissense: likely benign (0.1026); Very rare (popmax 0.0037%, nfe); Associated with Inborn genetic diseases.

What condition is associated with IDS p.Arg445Ser (c.1333C>A)?

IDS p.Arg445Ser (c.1333C>A) is associated with Inborn genetic diseases (ClinVar).

How common is IDS p.Arg445Ser (c.1333C>A) in the general population?

IDS p.Arg445Ser (c.1333C>A) is very rare (popmax 0.0037%, nfe) (gnomAD).

What do computational predictors say about IDS p.Arg445Ser (c.1333C>A)?

AlphaMissense predicts likely benign (score 0.1026) — an in-silico prediction, not a clinical call.

IDS p.Arg445Ser

c.1333C>A · VCV3768919

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1026 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0037%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1026	likely benign
REVEL	0.329	indeterminate
SaProt	LLR -5.02	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.98	GERP -1.6, phastCons 0.031
Regional constraint	o/e 0.78	unconstrained · MANE · 21 kb · p 5.6e-05 · regional, not allelic
Overall
CADD	3.45	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0037% European (non-Finnish) · 33/891,746 alleles

Filtering AF 0.00264% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00232%

Overall 0.00274% 33/1,205,152 alleles · very rare exomes 32/1,093,574 · genomes 1/111,578 · joint denominator

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: IDS
Protein: p.Arg445Ser
Coding: c.1333C>A
MANE Select: NM_000202
Type: single nucleotide variant
Location: chrX:149483066 (GRCh38)
Structure: AlphaFold pLDDT 93.39 · 2 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IDS p.Arg445His Conflicting classifications of pathogenicity ★ ⚠ same residue
IDS p.Arg445= Likely benign ★ same residue
IDS p.Arg445Cys Likely benign ★ same residue
IDS p.Arg172Ter Pathogenic ★★ same condition
IDS p.Asp269Val Pathogenic/Likely pathogenic ★★ same condition
IDS p.Pro469Arg Likely pathogenic ★★ same condition
IDS p.Ser71Arg Likely pathogenic ★★ same condition
IDS p.Tyr499Ter Pathogenic/Likely pathogenic ★★ same condition

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/ids-p-arg445ser (accessed [today's date]).

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