Is HPS3 p.Pro643Ser (c.1927C>T) pathogenic?

HPS3 p.Pro643Ser (c.1927C>T) is classified Uncertain significance in HPS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-19). AlphaMissense: ambiguous (0.4275); Very rare (popmax 8.48e-05%, nfe).

How common is HPS3 p.Pro643Ser (c.1927C>T) in the general population?

HPS3 p.Pro643Ser (c.1927C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about HPS3 p.Pro643Ser (c.1927C>T)?

AlphaMissense predicts ambiguous (score 0.4275) — an in-silico prediction, not a clinical call.

HPS3 p.Pro643Ser

c.1927C>T · rs1723695850 · VCV1480140

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4275 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4275	ambiguous
REVEL	0.336	indeterminate
SaProt	LLR -11.12	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 42 kb · p 0.79 · regional, not allelic
Overall
CADD	25.0	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 8.48e-05% European (non-Finnish) · 1/1,179,852 alleles

Overall 6.2e-05% 1/1,613,896 alleles · very rare exomes 1/1,461,628 · genomes 0/152,268 · 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.Pro643Ser
Coding: c.1927C>T
MANE Select: NM_032383
dbSNP: rs1723695850
Type: single nucleotide variant
Location: chr3:149160100 (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-pro643ser (accessed [today's date]).

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