Is HGD p.Pro359Ser (c.1075C>T) pathogenic?

HGD p.Pro359Ser (c.1075C>T) is classified Pathogenic in HGD (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely benign (0.3191); Absent from gnomAD v4.1; Associated with alkaptonuria.

What condition is associated with HGD p.Pro359Ser (c.1075C>T)?

HGD p.Pro359Ser (c.1075C>T) is associated with alkaptonuria (ClinVar).

How common is HGD p.Pro359Ser (c.1075C>T) in the general population?

HGD p.Pro359Ser (c.1075C>T) 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.Pro359Ser (c.1075C>T)?

AlphaMissense predicts likely benign (score 0.3191) — an in-silico prediction, not a clinical call.

HGD p.Pro359Ser

c.1075C>T · rs2472652226 · VCV2627704

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3191 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

alkaptonuria

Computational evidence

Protein change
AlphaMissense	0.3191	likely benign ⚠ discordant with ClinVar
REVEL	0.949	strongly pathogenic-leaning
SaProt	LLR -10.12	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 54 kb · p 0.73 · regional, not allelic
Overall
CADD	27.3	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.Pro359Ser
Coding: c.1075C>T
MANE Select: NM_000187
dbSNP: rs2472652226
Type: single nucleotide variant
Location: chr3:120633260 (GRCh38)
Gene constraint: LOEUF 1.199 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.85 · 2 PDB
Residue 359: a UniProt-annotated variant site (in aku)

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.Pro359Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro359ser (accessed [today's date]).

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