Is HPS4 p.Pro101Ser (c.301C>T) pathogenic?

HPS4 p.Pro101Ser (c.301C>T) is classified Uncertain significance in HPS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-01). AlphaMissense: likely benign (0.1431); Very rare (popmax 0.000847%, nfe); Associated with Inborn genetic diseases.

What condition is associated with HPS4 p.Pro101Ser (c.301C>T)?

HPS4 p.Pro101Ser (c.301C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HPS4 p.Pro101Ser (c.301C>T) in the general population?

HPS4 p.Pro101Ser (c.301C>T) is very rare (popmax 0.000847%, nfe) (gnomAD).

What do computational predictors say about HPS4 p.Pro101Ser (c.301C>T)?

AlphaMissense predicts likely benign (score 0.1431) — an in-silico prediction, not a clinical call.

HPS4 p.Pro101Ser

c.301C>T · rs775352863 · VCV2331612

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1431 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1431	likely benign
REVEL	0.45	indeterminate
SaProt	LLR -4.24	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.3	GERP -0.13, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 29 kb · p 0.7 · regional, not allelic
Overall
CADD	19.04	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 0.000847% European (non-Finnish) · 10/1,179,998 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.00062% 10/1,614,136 alleles · very rare exomes 10/1,461,880 · genomes 0/152,256 · 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: HPS4
Protein: p.Pro101Ser
Coding: c.301C>T
MANE Select: NM_022081
dbSNP: rs775352863
Type: single nucleotide variant
Location: chr22:26472915 (GRCh38)
Gene constraint: LOEUF 0.794 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.83 · 1 PDB

Full HPS4 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

HPS4 p.Pro101Leu Uncertain significance ★ ⚠ same residue
HPS4 p.Arg107Trp Uncertain significance ★★ ⚠ same condition
HPS4 p.Arg463Gly Uncertain significance ★★ ⚠ same condition
HPS4 p.Arg466His Uncertain significance ★★ ⚠ same condition
HPS4 p.Arg609His Uncertain significance ★★ ⚠ same condition
HPS4 p.Arg62Cys Uncertain significance ★★ ⚠ same condition
HPS4 p.Asp278Val Uncertain significance ★★ ⚠ same condition
HPS4 p.Asp31Asn 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/hps4-p-pro101ser (accessed [today's date]).

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