Is HGD p.Ser15Pro (c.43T>C) pathogenic?

HGD p.Ser15Pro (c.43T>C) is classified Uncertain significance in HGD (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-08). AlphaMissense: likely pathogenic (0.6781); Absent from gnomAD v4.1; Associated with alkaptonuria.

What condition is associated with HGD p.Ser15Pro (c.43T>C)?

HGD p.Ser15Pro (c.43T>C) is associated with alkaptonuria (ClinVar).

How common is HGD p.Ser15Pro (c.43T>C) in the general population?

HGD p.Ser15Pro (c.43T>C) is absent from gnomAD v4.1 (gnomAD).

How is Alkaptonuria inherited?

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

What do computational predictors say about HGD p.Ser15Pro (c.43T>C)?

AlphaMissense predicts likely pathogenic (score 0.6781) — an in-silico prediction, not a clinical call.

HGD p.Ser15Pro

c.43T>C · rs2107557717 · VCV1466513

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6781 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

alkaptonuria

Computational evidence

Protein change
AlphaMissense	0.6781	likely pathogenic
REVEL	0.507	indeterminate
SaProt	LLR -7.58	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.74	GERP -1.3, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 54 kb · p 0.73 · regional, not allelic
Overall
CADD	19.83	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

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: HGD
Protein: p.Ser15Pro
Coding: c.43T>C
MANE Select: NM_000187
dbSNP: rs2107557717
Type: single nucleotide variant
Location: chr3:120675836 (GRCh38)
Gene constraint: LOEUF 1.199 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.85 · 2 PDB
Residue 15: 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 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
HGD c.469+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/hgd-p-ser15pro (accessed [today's date]).

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