Is HPS3 p.Pro419Ser (c.1255C>T) pathogenic?

HPS3 p.Pro419Ser (c.1255C>T) is classified Uncertain significance in HPS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-26). AlphaMissense: likely benign (0.196); Absent from gnomAD v4.1.

How common is HPS3 p.Pro419Ser (c.1255C>T) in the general population?

HPS3 p.Pro419Ser (c.1255C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HPS3 p.Pro419Ser (c.1255C>T)?

AlphaMissense predicts likely benign (score 0.196) — an in-silico prediction, not a clinical call.

HPS3 p.Pro419Ser

c.1255C>T · rs2473099313 · VCV1951998

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.196 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.196	likely benign
REVEL	0.349	indeterminate
SaProt	LLR -5.89	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 42 kb · p 0.79 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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: HPS3
Protein: p.Pro419Ser
Coding: c.1255C>T
MANE Select: NM_032383
dbSNP: rs2473099313
Type: single nucleotide variant
Location: chr3:149153503 (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

Similar variants

HPS3 c.1163+1G>A Pathogenic ★★ same type
HPS3 c.1246-2A>T Likely pathogenic ★★ same type
HPS3 c.1509+1G>A Likely pathogenic ★★ same type
HPS3 c.1691+1G>A Pathogenic ★★ same type
HPS3 c.1692-2A>G Likely pathogenic ★★ same type
HPS3 c.1873-1G>A Likely pathogenic ★★ same type
HPS3 c.2106+1G>T Likely pathogenic ★★ same type
HPS3 c.2292+1G>A Likely pathogenic ★★ same type

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-pro419ser (accessed [today's date]).

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