Is GALNS p.Pro57Ser (c.169C>T) pathogenic?

GALNS p.Pro57Ser (c.169C>T) is classified Uncertain significance in GALNS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-22). AlphaMissense: likely benign (0.2428); Ultra-rare (popmax 0.0822%, mid); Associated with mucopolysaccharidosis type 4A.

What condition is associated with GALNS p.Pro57Ser (c.169C>T)?

GALNS p.Pro57Ser (c.169C>T) is associated with mucopolysaccharidosis type 4A (ClinVar).

How common is GALNS p.Pro57Ser (c.169C>T) in the general population?

GALNS p.Pro57Ser (c.169C>T) is ultra-rare (popmax 0.0822%, mid) (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.Pro57Ser (c.169C>T)?

AlphaMissense predicts likely benign (score 0.2428) — an in-silico prediction, not a clinical call.

GALNS p.Pro57Ser

c.169C>T · rs759564640 · VCV2627276

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2428 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0822%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mucopolysaccharidosis type 4A

Computational evidence

Protein change
AlphaMissense	0.2428	likely benign
REVEL	0.981	strongly pathogenic-leaning
SaProt	LLR -12.13	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.2, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 42 kb · p 0.0044 · regional, not allelic
Overall
CADD	26.2	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 0.0822% Middle Eastern · 5/6,082 alleles

Filtering AF 0.0323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.000372% 6/1,613,192 alleles · ultra-rare exomes 5/1,460,976 · genomes 1/152,216 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0822%	1,216
East Asian	0.00223%	44,872

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: GALNS
Protein: p.Pro57Ser
Coding: c.169C>T
MANE Select: NM_000512
dbSNP: rs759564640
Type: single nucleotide variant
Location: chr16:88842781 (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 57: an α-helix; the 'catalytic domain' region

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 p.Pro57Leu Uncertain significance ★★ ⚠ same residue
GALNS p.Pro57= Likely benign ★ same residue
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

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-pro57ser (accessed [today's date]).

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