Is HPS3 p.Ala416Pro (c.1246G>C) pathogenic?

HPS3 p.Ala416Pro (c.1246G>C) is classified Uncertain significance in HPS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-21). AlphaMissense: likely pathogenic (0.8835); Ultra-rare (popmax 0.0176%, sas).

How common is HPS3 p.Ala416Pro (c.1246G>C) in the general population?

HPS3 p.Ala416Pro (c.1246G>C) is ultra-rare (popmax 0.0176%, sas) (gnomAD).

What do computational predictors say about HPS3 p.Ala416Pro (c.1246G>C)?

AlphaMissense predicts likely pathogenic (score 0.8835) — an in-silico prediction, not a clinical call.

HPS3 p.Ala416Pro

c.1246G>C · rs567188396 · VCV2201898

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8835 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8835	likely pathogenic · top 6% in HPS3
REVEL	0.498	indeterminate
SaProt	LLR -0.99	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.23	acceptor loss at this position · masked 0 · deltas
Pangolin	Δ0.34	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 42 kb · p 0.79 · regional, not allelic
Overall
CADD	29.6	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

Grpmax group 0.0176% South Asian · 16/91,048 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00409% 66/1,613,200 alleles · ultra-rare exomes 61/1,460,980 · genomes 5/152,220 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0176%	5,691
European (non-Finnish)	0.0039%	25,635
Remaining individualsnot grpmax-eligible	0.0032%	31,242
African / African-American	0.00267%	37,504

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.Ala416Pro
Coding: c.1246G>C
MANE Select: NM_032383
dbSNP: rs567188396
Type: single nucleotide variant
Location: chr3:149153494 (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.Ala416fs Pathogenic/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
HPS3 c.2106+1G>T 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-ala416pro (accessed [today's date]).

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