Is HPS5 p.Arg375Pro (c.1124G>C) pathogenic?

HPS5 p.Arg375Pro (c.1124G>C) is classified Uncertain significance in HPS5 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-21). AlphaMissense: likely pathogenic (0.7647); Absent from gnomAD v4.1.

How common is HPS5 p.Arg375Pro (c.1124G>C) in the general population?

HPS5 p.Arg375Pro (c.1124G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HPS5 p.Arg375Pro (c.1124G>C)?

AlphaMissense predicts likely pathogenic (score 0.7647) — an in-silico prediction, not a clinical call.

HPS5 p.Arg375Pro

c.1124G>C · rs749923910 · VCV1467897

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7647 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7647	likely pathogenic
REVEL	0.212	benign-leaning
SaProt	LLR -12.59	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.71	GERP -5.6, phastCons 0.001
Regional constraint	o/e 0.97	unconstrained · MANE · 38 kb · p 0.21 · regional, not allelic
Overall
CADD	13.19	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

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: HPS5
Protein: p.Arg375Pro
Coding: c.1124G>C
MANE Select: NM_181507
dbSNP: rs749923910
Type: single nucleotide variant
Location: chr11:18298832 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.21

Full HPS5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HPS5 p.Arg375Cys Uncertain significance ★ ⚠ same residue
HPS5 p.Arg375Gly Uncertain significance ★ ⚠ same residue
HPS5 c.1164+1G>A Likely pathogenic ★★ same type
HPS5 c.1862+1G>A Likely pathogenic ★★ same type
HPS5 c.220-1G>T Pathogenic ★★ same type
HPS5 c.2718-2A>G Pathogenic/Likely pathogenic ★★ same type
HPS5 c.2837+1G>A Likely pathogenic ★★ same type
HPS5 c.2952-1G>C 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/hps5-p-arg375pro (accessed [today's date]).

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