Is HPD p.Phe368Leu (c.1104C>A) pathogenic?

HPD p.Phe368Leu (c.1104C>A) is classified Uncertain significance in HPD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-25). AlphaMissense: likely pathogenic (0.9958); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with HPD p.Phe368Leu (c.1104C>A)?

HPD p.Phe368Leu (c.1104C>A) is associated with Inborn genetic diseases (ClinVar).

How common is HPD p.Phe368Leu (c.1104C>A) in the general population?

HPD p.Phe368Leu (c.1104C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HPD p.Phe368Leu (c.1104C>A)?

AlphaMissense predicts likely pathogenic (score 0.9958) — an in-silico prediction, not a clinical call.

HPD p.Phe368Leu

c.1104C>A · rs1472186566 · VCV2478968

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9958 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9958	likely pathogenic · top 1% in HPD
REVEL	0.79	moderately pathogenic-leaning
SaProt	LLR -11.58	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.84, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 19 kb · p 0.004 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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: HPD
Protein: p.Phe368Leu
Coding: c.1104C>A
MANE Select: NM_002150
dbSNP: rs1472186566
Type: single nucleotide variant
Location: chr12:121839806 (GRCh38)
Gene constraint: LOEUF 0.845 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 4 PDB
Residue 368: a UniProt-annotated variant site (in tyrsn3; likely pathogenic); an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HPD p.Phe368= Likely benign ★ same residue
HPD c.198+3G>A Uncertain significance ★★ same condition
HPD p.Arg279Cys Uncertain significance ★★ ⚠ same condition
HPD p.Arg300Trp Uncertain significance ★★ ⚠ same condition
HPD p.Asp182Glu Uncertain significance ★★ ⚠ same condition
HPD p.Gly159Glu Uncertain significance ★★ ⚠ same condition
HPD p.Thr2Met Uncertain significance ★★ ⚠ same condition
HPD p.Asp167Asn Benign/Likely benign ★★ ⚠ 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-phe368leu (accessed [today's date]).

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