Is HPS5 p.Ile172Met (c.516C>G) pathogenic?

HPS5 p.Ile172Met (c.516C>G) is classified Uncertain significance in HPS5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely benign (0.2273); Very rare (popmax 0.00533%, afr); Associated with Inborn genetic diseases.

What condition is associated with HPS5 p.Ile172Met (c.516C>G)?

HPS5 p.Ile172Met (c.516C>G) is associated with Inborn genetic diseases (ClinVar).

How common is HPS5 p.Ile172Met (c.516C>G) in the general population?

HPS5 p.Ile172Met (c.516C>G) is very rare (popmax 0.00533%, afr) (gnomAD).

What do computational predictors say about HPS5 p.Ile172Met (c.516C>G)?

AlphaMissense predicts likely benign (score 0.2273) — an in-silico prediction, not a clinical call.

HPS5 p.Ile172Met

c.516C>G · VCV4621710

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2273 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00533%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2273	likely benign
REVEL	0.287	benign-leaning
SaProt	LLR -9.46	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 1.6	GERP -0.76, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 38 kb · p 0.21 · regional, not allelic
Overall
CADD	20.8	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 0.00533% African / African-American · 4/75,034 alleles

Filtering AF 0.00174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000496% 8/1,613,828 alleles · very rare exomes 7/1,461,538 · genomes 1/152,290 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00533%	18,758
Remaining individualsnot grpmax-eligible	0.0032%	31,250
South Asian	0.0011%	91,070
European (non-Finnish)	8.48e-05%	1,179,760

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: HPS5
Protein: p.Ile172Met
Coding: c.516C>G
MANE Select: NM_181507
Type: single nucleotide variant
Location: chr11:18309041 (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

Disease context

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

Similar variants

HPS5 p.Ile172Val Uncertain significance ★★ ⚠ same residue
HPS5 p.Ile172= Likely benign ★ same residue
HPS5 p.Arg108His Uncertain significance ★★ ⚠ same condition
HPS5 p.Arg108Leu Uncertain significance ★★ ⚠ same condition
HPS5 p.Arg1122Gln Uncertain significance ★★ ⚠ same condition
HPS5 p.Arg1122Trp Uncertain significance ★★ ⚠ same condition
HPS5 p.Arg29Trp Uncertain significance ★★ same condition
HPS5 p.Arg359His 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/hps5-p-ile172met (accessed [today's date]).

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