Is IDS p.Val223Ile (c.667G>A) pathogenic?

IDS p.Val223Ile (c.667G>A) is classified Benign/Likely benign in IDS (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-16). AlphaMissense: likely benign (0.0796); Rare (popmax 0.161%, mid); Associated with mucopolysaccharidosis type 2.

What condition is associated with IDS p.Val223Ile (c.667G>A)?

IDS p.Val223Ile (c.667G>A) is associated with mucopolysaccharidosis type 2 (ClinVar).

How common is IDS p.Val223Ile (c.667G>A) in the general population?

IDS p.Val223Ile (c.667G>A) is rare (popmax 0.161%, mid) (gnomAD).

How is Mucopolysaccharidosis type 2 inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about IDS p.Val223Ile (c.667G>A)?

AlphaMissense predicts likely benign (score 0.0796) — an in-silico prediction, not a clinical call.

IDS p.Val223Ile

c.667G>A · rs200784263 · VCV377971

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0796 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.161%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mucopolysaccharidosis type 2

Computational evidence

Protein change
AlphaMissense	0.0796	likely benign
REVEL	0.673	pathogenic-leaning
SaProt	LLR -8.41	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.78	GERP -0.74, phastCons 0.22
Regional constraint	o/e 0.78	unconstrained · MANE · 21 kb · p 5.6e-05 · regional, not allelic
Overall
CADD	23.4	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 0.161% Middle Eastern · 7/4,352 alleles

Filtering AF 0.0754% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0535%

Overall 0.00719% 87/1,209,759 alleles · rare exomes 71/1,097,802 · genomes 16/111,957 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.161%	622
Admixed American	0.0218%	4,585
Remaining individualsnot grpmax-eligible	0.0105%	9,520
African / African-American	0.0105%	9,527
European (non-Finnish)	0.00648%	15,430
South Asian	0.00176%	56,813

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.Val223Ile
Coding: c.667G>A
MANE Select: NM_000202
dbSNP: rs200784263
Type: single nucleotide variant
Location: chrX:149498148 (GRCh38)
Structure: AlphaFold pLDDT 93.39 · 2 PDB
Residue 223: a β-strand

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

Disease context

mucopolysaccharidosis type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mucopolysaccharidosis type 2 (Orphanet):

Inheritance: X-linked recessive
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

IDS p.Val223= Likely benign ★ same residue
IDS p.Val223fs Pathogenic ★ same residue
IDS p.Val223Phe Uncertain significance ★ ⚠ same residue
IDS c.1006+1G>C Pathogenic ★★ same condition
IDS c.1006+1G>T Pathogenic ★★ same condition
IDS c.1007-133A>G Likely pathogenic ★★ same condition
IDS c.1007-1G>A Pathogenic ★★ same condition
IDS c.1007-2A>C 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-val223ile (accessed [today's date]).

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