Is HGD p.Ser47= (c.141G>A) pathogenic?

HGD p.Ser47= (c.141G>A) is classified Conflicting classifications of pathogenicity in HGD (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-02-17). Ultra-rare (popmax 0.0415%, nfe); Associated with alkaptonuria.

What condition is associated with HGD p.Ser47= (c.141G>A)?

HGD p.Ser47= (c.141G>A) is associated with alkaptonuria (ClinVar).

How common is HGD p.Ser47= (c.141G>A) in the general population?

HGD p.Ser47= (c.141G>A) is ultra-rare (popmax 0.0415%, nfe) (gnomAD).

How is Alkaptonuria inherited?

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

HGD p.Ser47=

c.141G>A · rs541268108 · VCV342754

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0415%, nfe)

Conditions

alkaptonuria

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 -5.6	GERP -5.4
Overall
CADD	2.67	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0415% European (non-Finnish) · 489/1,178,302 alleles

Filtering AF 0.0384% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0372%

Overall 0.0326% 526/1,611,916 alleles · ultra-rare exomes 509/1,459,700 · genomes 17/152,216 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0415%	2,410
Remaining individualsnot grpmax-eligible	0.0224%	4,456
South Asian	0.0187%	5,356
Middle Eastern	0.0166%	6,042
African / African-American	0.00534%	18,732
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,530

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: HGD
Protein: p.Ser47=
Coding: c.141G>A
MANE Select: NM_000187
dbSNP: rs541268108
Type: single nucleotide variant
Location: chr3:120674936 (GRCh38)
Gene constraint: LOEUF 1.199 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.85 · 2 PDB
Residue 47: a β-strand

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

Disease context

alkaptonuria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Alkaptonuria (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult, Infancy
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

HGD p.Ser47Leu Likely pathogenic ★ same residue
HGD c.1007-2A>T Pathogenic ★★ same condition
HGD c.1188+1G>A Pathogenic ★★ same condition
HGD c.15+1G>A Pathogenic/Likely pathogenic ★★ same condition
HGD c.16-1G>A Pathogenic ★★ same condition
HGD c.342+1G>A Pathogenic/Likely pathogenic ★★ same condition
HGD c.342+1G>T Pathogenic ★★ same condition
HGD c.342+3A>C Pathogenic/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/hgd-p-ser47 (accessed [today's date]).

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