Is HGD p.Pro103Thr (c.307C>A) pathogenic?

HGD p.Pro103Thr (c.307C>A) is classified Conflicting classifications of pathogenicity in HGD (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-02-22). AlphaMissense: likely benign (0.1944); Rare (popmax 0.287%, sas); Associated with alkaptonuria.

What condition is associated with HGD p.Pro103Thr (c.307C>A)?

HGD p.Pro103Thr (c.307C>A) is associated with alkaptonuria (ClinVar).

How common is HGD p.Pro103Thr (c.307C>A) in the general population?

HGD p.Pro103Thr (c.307C>A) is rare (popmax 0.287%, sas) (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.Pro103Thr (c.307C>A)?

AlphaMissense predicts likely benign (score 0.1944) — an in-silico prediction, not a clinical call.

HGD p.Pro103Thr

c.307C>A · rs559502955 · VCV342751

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1944 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.287%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

alkaptonuria

Computational evidence

Protein change
AlphaMissense	0.1944	likely benign
REVEL	0.673	pathogenic-leaning
SaProt	LLR -11.87	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 54 kb · p 0.73 · regional, not allelic
Overall
CADD	24.5	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

Grpmax group 0.287% South Asian · 261/91,006 alleles

Filtering AF 0.258% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.247%

Overall 0.0176% 284/1,613,160 alleles · rare exomes 259/1,461,044 · genomes 25/152,116 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.287%	349
Remaining individualsnot grpmax-eligible	0.024%	4,165
Middle Eastern	0.0166%	6,040
East Asian	0.00223%	44,832
European (non-Finnish)	0.000509%	196,563

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.Pro103Thr
Coding: c.307C>A
MANE Select: NM_000187
dbSNP: rs559502955
Type: single nucleotide variant
Location: chr3:120652627 (GRCh38)
Gene constraint: LOEUF 1.199 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.85 · 2 PDB
Residue 103: an α-helix

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.Pro103fs 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-pro103thr (accessed [today's date]).

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