Is HPS1 p.Ser403Pro (c.1207T>C) pathogenic?

HPS1 p.Ser403Pro (c.1207T>C) is classified Uncertain significance in HPS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely pathogenic (0.5743); Very rare (popmax 0.00833%, amr).

How common is HPS1 p.Ser403Pro (c.1207T>C) in the general population?

HPS1 p.Ser403Pro (c.1207T>C) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about HPS1 p.Ser403Pro (c.1207T>C)?

AlphaMissense predicts likely pathogenic (score 0.5743) — an in-silico prediction, not a clinical call.

HPS1 p.Ser403Pro

c.1207T>C · rs755979374 · VCV1436532

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5743 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5743	likely pathogenic
REVEL	0.188	benign-leaning
SaProt	LLR -11.48	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 0.56, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 26 kb · p 0.11 · regional, not allelic
Overall
CADD	13.33	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 0.00833% Admixed American · 5/60,002 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000806% 13/1,613,386 alleles · very rare exomes 10/1,461,184 · genomes 3/152,202 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,000
European (non-Finnish)	0.000678%	147,487

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: HPS1
Protein: p.Ser403Pro
Coding: c.1207T>C
MANE Select: NM_000195
dbSNP: rs755979374
Type: single nucleotide variant
Location: chr10:98425669 (GRCh38)
Gene constraint: LOEUF 0.879 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.44 · 1 PDB

Full HPS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HPS1 c.1335+1G>A Likely pathogenic ★★ same type
HPS1 c.1744-2A>C Pathogenic/Likely pathogenic ★★ same type
HPS1 c.1857+1G>A Likely pathogenic ★★ same type
HPS1 c.1857+2T>C Pathogenic/Likely pathogenic ★★ same type
HPS1 c.1858-1G>A Pathogenic/Likely pathogenic ★★ same type
HPS1 c.1940+1G>A Pathogenic/Likely pathogenic ★★ same type
HPS1 c.1940+2T>C Pathogenic/Likely pathogenic ★★ same type
HPS1 c.398+2T>C Pathogenic/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/hps1-p-ser403pro (accessed [today's date]).

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