Is IDS p.Ser539Phe (c.1616C>T) pathogenic?

IDS p.Ser539Phe (c.1616C>T) is classified Uncertain significance in IDS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-28). AlphaMissense: likely benign (0.0995); Very rare (popmax 0.000223%, nfe).

How common is IDS p.Ser539Phe (c.1616C>T) in the general population?

IDS p.Ser539Phe (c.1616C>T) is very rare (popmax 0.000223%, nfe) (gnomAD).

What do computational predictors say about IDS p.Ser539Phe (c.1616C>T)?

AlphaMissense predicts likely benign (score 0.0995) — an in-silico prediction, not a clinical call.

IDS p.Ser539Phe

c.1616C>T · VCV4088131

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0995 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000223%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0995	likely benign
REVEL	0.365	indeterminate
SaProt	LLR -1.81	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 21 kb · p 5.6e-05 · regional, not allelic
Overall
CADD	19.55	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 0.000223% European (non-Finnish) · 2/895,522 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000165% 2/1,211,647 alleles · very rare exomes 2/1,098,233 · genomes 0/113,414 · 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.Ser539Phe
Coding: c.1616C>T
MANE Select: NM_000202
Type: single nucleotide variant
Location: chrX:149482783 (GRCh38)
Structure: AlphaFold pLDDT 93.39 · 2 PDB

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

Similar variants

IDS p.Ser539= Likely benign ★ 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
IDS c.1007-8T>G Pathogenic/Likely pathogenic ★★ same type
IDS c.103+1G>A 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-ser539phe (accessed [today's date]).

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