Is HPS3 p.Arg220Ser (c.660A>T) pathogenic?

HPS3 p.Arg220Ser (c.660A>T) is classified Uncertain significance in HPS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-16). AlphaMissense: likely benign (0.096); Very rare (popmax 0.00348%, nfe).

How common is HPS3 p.Arg220Ser (c.660A>T) in the general population?

HPS3 p.Arg220Ser (c.660A>T) is very rare (popmax 0.00348%, nfe) (gnomAD).

What do computational predictors say about HPS3 p.Arg220Ser (c.660A>T)?

AlphaMissense predicts likely benign (score 0.096) — an in-silico prediction, not a clinical call.

HPS3 p.Arg220Ser

c.660A>T · rs760546363 · VCV2165398

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.096 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00348%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.096	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -4.92	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 1.1	GERP -3.5, phastCons 0.65
Regional constraint	o/e 0.99	unconstrained · MANE · 42 kb · p 0.79 · regional, not allelic
Overall
CADD	5.048	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 0.00348% European (non-Finnish) · 41/1,179,684 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00273% 44/1,612,950 alleles · very rare exomes 42/1,460,768 · genomes 2/152,182 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00348%	28,773
Remaining individualsnot grpmax-eligible	0.0032%	31,219
Finnishnot grpmax-eligible	0.00156%	64,028

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.Arg220Ser
Coding: c.660A>T
MANE Select: NM_032383
dbSNP: rs760546363
Type: single nucleotide variant
Location: chr3:149140446 (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 p.Arg220= Likely benign ★ same residue
HPS3 p.Arg220fs Likely pathogenic ★ same residue
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

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-arg220ser (accessed [today's date]).

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