Is HGD p.Pro331= (c.993T>C) pathogenic?

HGD p.Pro331= (c.993T>C) is classified Likely benign in HGD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-11). Rare (popmax 0.132%, mid); Associated with alkaptonuria.

What condition is associated with HGD p.Pro331= (c.993T>C)?

HGD p.Pro331= (c.993T>C) is associated with alkaptonuria (ClinVar).

How common is HGD p.Pro331= (c.993T>C) in the general population?

HGD p.Pro331= (c.993T>C) is rare (popmax 0.132%, mid) (gnomAD).

How is Alkaptonuria inherited?

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

HGD p.Pro331=

c.993T>C · rs747288180 · VCV716752

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.132%, mid)

Conditions

alkaptonuria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.027	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 0.57, phastCons 1
Overall
CADD	10.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.132% Middle Eastern · 8/6,082 alleles

Filtering AF 0.0654% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0528%

Overall 0.00793% 128/1,613,838 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.132%	760
Admixed American	0.0767%	1,304
South Asian	0.022%	4,554
Remaining individualsnot grpmax-eligible	0.0128%	7,810
European (non-Finnish)	0.00373%	26,816
African / African-American	0.00267%	37,445

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.Pro331=
Coding: c.993T>C
MANE Select: NM_000187
dbSNP: rs747288180
Type: single nucleotide variant
Location: chr3:120638468 (GRCh38)
Gene constraint: LOEUF 1.199 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.85 · 2 PDB

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-pro331 (accessed [today's date]).

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