Is GALNS p.Phe346= (c.1038C>T) pathogenic?

GALNS p.Phe346= (c.1038C>T) is classified Likely benign in GALNS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-10). Very rare (popmax 0.00227%, eas); Associated with mucopolysaccharidosis type 4A.

What condition is associated with GALNS p.Phe346= (c.1038C>T)?

GALNS p.Phe346= (c.1038C>T) is associated with mucopolysaccharidosis type 4A (ClinVar).

How common is GALNS p.Phe346= (c.1038C>T) in the general population?

GALNS p.Phe346= (c.1038C>T) is very rare (popmax 0.00227%, eas) (gnomAD).

How is Mucopolysaccharidosis type 4 inherited?

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

GALNS p.Phe346=

c.1038C>T · rs766504053 · VCV2894188

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00227%, eas)

Conditions

mucopolysaccharidosis type 4A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP -0.85, phastCons 1
Overall
CADD	9.397	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00227% East Asian · 1/43,976 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000313% 5/1,596,298 alleles · very rare exomes 5/1,443,952 · genomes 0/152,346 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00227%	43,976
European (non-Finnish)	0.000341%	293,044

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.Phe346=
Coding: c.1038C>T
MANE Select: NM_000512
dbSNP: rs766504053
Type: single nucleotide variant
Location: chr16:88826803 (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 346: a UniProt-annotated variant site (in mps4a; severe form); 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.Phe346Leu Uncertain significance ★ ⚠ 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
GALNS c.1365-1G>C 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-phe346 (accessed [today's date]).

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