Is HPD p.Met166Ile (c.498G>A) pathogenic?

HPD p.Met166Ile (c.498G>A) is classified Conflicting classifications of pathogenicity in HPD (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0951); Rare (popmax 0.277%, nfe); Associated with hawkinsinuria.

What condition is associated with HPD p.Met166Ile (c.498G>A)?

HPD p.Met166Ile (c.498G>A) is associated with hawkinsinuria, tyrosinemia type III (ClinVar).

How common is HPD p.Met166Ile (c.498G>A) in the general population?

HPD p.Met166Ile (c.498G>A) is rare (popmax 0.277%, nfe) (gnomAD).

How is Hawkinsinuria inherited?

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

What do computational predictors say about HPD p.Met166Ile (c.498G>A)?

AlphaMissense predicts likely benign (score 0.0951) — an in-silico prediction, not a clinical call.

HPD p.Met166Ile

c.498G>A · rs149081239 · VCV307484

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0951 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.277%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hawkinsinuria

Computational evidence

Protein change
AlphaMissense	0.0951	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -3.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.42	GERP -1.6, phastCons 0.031
Regional constraint	o/e 0.87	unconstrained · MANE · 19 kb · p 0.004 · regional, not allelic
Overall
CADD	7.715	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 0.277% European (non-Finnish) · 3,268/1,179,072 alleles

Filtering AF 0.269% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.266%

Overall 0.217% 3,499/1,613,028 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.277%	361
Remaining individualsnot grpmax-eligible	0.15%	665
Finnishnot grpmax-eligible	0.0609%	1,641
African / African-American	0.0573%	1,744
South Asian	0.0406%	2,461
Admixed American	0.03%	3,333

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: HPD
Protein: p.Met166Ile
Coding: c.498G>A
MANE Select: NM_002150
dbSNP: rs149081239
Type: single nucleotide variant
Location: chr12:121849707 (GRCh38)
Gene constraint: LOEUF 0.845 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 4 PDB

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

Disease context

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

Also linked: tyrosinemia type III

For Hawkinsinuria (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

HPD p.Met166Thr Uncertain significance ★ ⚠ same residue
HPD p.Met166Val Uncertain significance ★ ⚠ same residue
HPD p.Arg225Ter Pathogenic/Likely pathogenic ★★ same condition
HPD p.Gln205Ter Pathogenic/Likely pathogenic ★★ same condition
HPD p.Tyr160Cys Likely pathogenic ★★ ⚠ same condition
HPD p.Ala230Thr Uncertain significance ★★ ⚠ same condition
HPD p.Arg111Trp Uncertain significance ★★ ⚠ same condition
HPD p.Arg119Gln Uncertain significance ★★ ⚠ 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/hpd-p-met166ile (accessed [today's date]).

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