Is IDS p.Val223Phe (c.667G>T) pathogenic?

IDS p.Val223Phe (c.667G>T) is classified Uncertain significance in IDS (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-14). AlphaMissense: ambiguous (0.55); Absent from gnomAD v4.1.

How common is IDS p.Val223Phe (c.667G>T) in the general population?

IDS p.Val223Phe (c.667G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about IDS p.Val223Phe (c.667G>T)?

AlphaMissense predicts ambiguous (score 0.55) — an in-silico prediction, not a clinical call.

IDS p.Val223Phe

c.667G>T · rs200784263 · VCV2430992

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.55 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.55	ambiguous
REVEL	0.93	moderately pathogenic-leaning
SaProt	LLR -14.13	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 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	24.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: IDS
Protein: p.Val223Phe
Coding: c.667G>T
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

Similar variants

IDS p.Val223Ile Benign/Likely benign ★★ ⚠ same residue
IDS p.Val223= Likely benign ★ same residue
IDS p.Val223fs Pathogenic ★ same residue
IDS c.1006+1G>C Pathogenic ★★ same type
IDS c.1006+1G>T Pathogenic ★★ same type
IDS c.1007-133A>G Likely pathogenic ★★ same type
IDS c.1007-1G>A Pathogenic ★★ same type
IDS c.1007-2A>C Pathogenic/Likely pathogenic ★★ 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/ids-p-val223phe (accessed [today's date]).

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