Is HPS1 p.Ser346Pro (c.1036T>C) pathogenic?

HPS1 p.Ser346Pro (c.1036T>C) is classified Uncertain significance in HPS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-14). AlphaMissense: likely benign (0.0798); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with HPS1 p.Ser346Pro (c.1036T>C)?

HPS1 p.Ser346Pro (c.1036T>C) is associated with Inborn genetic diseases (ClinVar).

How common is HPS1 p.Ser346Pro (c.1036T>C) in the general population?

HPS1 p.Ser346Pro (c.1036T>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about HPS1 p.Ser346Pro (c.1036T>C)?

AlphaMissense predicts likely benign (score 0.0798) — an in-silico prediction, not a clinical call.

HPS1 p.Ser346Pro

c.1036T>C · rs2136157183 · VCV1501755

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0798 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0798	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -5.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP 0.55, phastCons 0.22
Regional constraint	o/e 0.95	unconstrained · MANE · 26 kb · p 0.11 · regional, not allelic
Overall
CADD	14.04	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

Grpmax group 0.00333% Admixed American · 2/60,026 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,614,112 alleles · very rare exomes 2/1,461,836 · genomes 0/152,276 · 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: HPS1
Protein: p.Ser346Pro
Coding: c.1036T>C
MANE Select: NM_000195
dbSNP: rs2136157183
Type: single nucleotide variant
Location: chr10:98425937 (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

Disease context

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

Similar variants

HPS1 p.Ser346= Likely benign ★★ same residue
HPS1 p.Arg107Trp Uncertain significance ★★ ⚠ same condition
HPS1 p.Arg135Trp Uncertain significance ★★ same condition
HPS1 p.Arg142Cys Uncertain significance ★★ ⚠ same condition
HPS1 p.Arg189Gln Uncertain significance ★★ ⚠ same condition
HPS1 p.Arg189Trp Uncertain significance ★★ ⚠ same condition
HPS1 p.Arg201Gln Uncertain significance ★★ ⚠ same condition
HPS1 p.Arg201Trp 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/hps1-p-ser346pro (accessed [today's date]).

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