Is HPS3 p.Cys142Phe (c.425G>T) pathogenic?

HPS3 p.Cys142Phe (c.425G>T) is classified Uncertain significance in HPS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-19). AlphaMissense: likely pathogenic (0.8216); Ultra-rare (popmax 0.012%, afr); Associated with Inborn genetic diseases.

What condition is associated with HPS3 p.Cys142Phe (c.425G>T)?

HPS3 p.Cys142Phe (c.425G>T) is associated with Inborn genetic diseases (ClinVar).

How common is HPS3 p.Cys142Phe (c.425G>T) in the general population?

HPS3 p.Cys142Phe (c.425G>T) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about HPS3 p.Cys142Phe (c.425G>T)?

AlphaMissense predicts likely pathogenic (score 0.8216) — an in-silico prediction, not a clinical call.

HPS3 p.Cys142Phe

c.425G>T · rs758281135 · VCV3106836

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8216 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8216	likely pathogenic · top 8% in HPS3
REVEL	0.935	strongly pathogenic-leaning
SaProt	LLR -13.43	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 42 kb · p 0.79 · regional, not allelic
Overall
CADD	28.1	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

Grpmax group 0.012% African / African-American · 9/74,894 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.000558% 9/1,613,974 alleles · ultra-rare exomes 2/1,461,868 · genomes 7/152,106 · joint denominator

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: HPS3
Protein: p.Cys142Phe
Coding: c.425G>T
MANE Select: NM_032383
dbSNP: rs758281135
Type: single nucleotide variant
Location: chr3:149140211 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.67

Full HPS3 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

HPS3 p.Ala401Val Uncertain significance ★★ ⚠ same condition
HPS3 p.Ala482Pro Uncertain significance ★★ ⚠ same condition
HPS3 p.Arg66Cys Uncertain significance ★★ ⚠ same condition
HPS3 p.Arg89Cys Uncertain significance ★★ ⚠ same condition
HPS3 p.Arg89His Uncertain significance ★★ ⚠ same condition
HPS3 p.Cys254Arg Uncertain significance ★★ ⚠ same condition
HPS3 p.Cys425Tyr Uncertain significance ★★ ⚠ same condition
HPS3 p.Gln461Pro 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/hps3-p-cys142phe (accessed [today's date]).

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