Is GALNS p.Ser74Phe (c.221C>T) pathogenic?

GALNS p.Ser74Phe (c.221C>T) is classified Uncertain significance in GALNS (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-01). AlphaMissense: likely pathogenic (0.8717); Absent from gnomAD v4.1; Associated with mucopolysaccharidosis type 4A.

What condition is associated with GALNS p.Ser74Phe (c.221C>T)?

GALNS p.Ser74Phe (c.221C>T) is associated with mucopolysaccharidosis type 4A (ClinVar).

How common is GALNS p.Ser74Phe (c.221C>T) in the general population?

GALNS p.Ser74Phe (c.221C>T) is absent from gnomAD v4.1 (gnomAD).

How is Mucopolysaccharidosis type 4 inherited?

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

What do computational predictors say about GALNS p.Ser74Phe (c.221C>T)?

AlphaMissense predicts likely pathogenic (score 0.8717) — an in-silico prediction, not a clinical call.

GALNS p.Ser74Phe

c.221C>T · rs2143005475 · VCV1048383

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8717 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mucopolysaccharidosis type 4A

Computational evidence

Protein change
AlphaMissense	0.8717	likely pathogenic
REVEL	0.841	moderately pathogenic-leaning
SaProt	LLR -13.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 42 kb · p 0.0044 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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: GALNS
Protein: p.Ser74Phe
Coding: c.221C>T
MANE Select: NM_000512
dbSNP: rs2143005475
Type: single nucleotide variant
Location: chr16:88842729 (GRCh38)
Gene constraint: LOEUF 1.251 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.04 · 2 PDB
Residue 74: the 'catalytic domain' region; a UniProt-annotated variant site (in mps4a); a UniProt-annotated variant site (in)

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

Disease context

mucopolysaccharidosis type 4A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mucopolysaccharidosis type 4 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy
Prevalence: <1 / 1 000 000 (Sweden)

Similar variants

GALNS c.1139+1G>A Pathogenic ★★ same condition
GALNS c.121-1G>A Pathogenic ★★ same condition
GALNS c.121-2A>G Pathogenic/Likely pathogenic ★★ same condition
GALNS c.1242+1G>C Pathogenic/Likely pathogenic ★★ same condition
GALNS c.1243-2A>C Likely pathogenic ★★ same condition
GALNS c.1364+1G>A Pathogenic ★★ same condition
GALNS c.1365-1G>C Pathogenic ★★ same condition
GALNS c.244+1G>A 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/galns-p-ser74phe (accessed [today's date]).

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