Is PCSK6 p.Ala33= (c.99G>T) pathogenic?

PCSK6 p.Ala33= (c.99G>T) is classified Likely benign in PCSK6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-01). Very rare (popmax 0.000766%, nfe).

How common is PCSK6 p.Ala33= (c.99G>T) in the general population?

PCSK6 p.Ala33= (c.99G>T) is very rare (popmax 0.000766%, nfe) (gnomAD).

PCSK6 p.Ala33=

c.99G>T · rs1193286721 · VCV2645758

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000766%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.16	GERP -1.1, phastCons 0.003
Overall
CADD	6.917	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000766% European (non-Finnish) · 6/783,156 alleles

Filtering AF 0.000276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000181%

Overall 0.000665% 6/901,836 alleles · very rare exomes 4/781,436 · genomes 2/120,400 · 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: PCSK6
Protein: p.Ala33=
Coding: c.99G>T
MANE Select: NM_002570
dbSNP: rs1193286721
Type: single nucleotide variant
Location: chr15:101489572 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.84
Residue 33: the 'disordered' region

Full PCSK6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PCSK6 c.1533-6C>G Benign ★★ same type
PCSK6 p.Ala867Val Likely benign ★★ same type
PCSK6 p.Pro455= Benign ★★ same type
PCSK6 p.Thr964Met Likely benign ★★ same type
PCSK6 p.Asn161= Conflicting classifications of pathogenicity ★ same type
PCSK6 p.Pro3Leu Uncertain significance ★ ⚠ same type
PCSK6 p.Ala529= Likely benign ★ same type
PCSK6 p.Asp309= Likely benign ★ 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/pcsk6-p-ala33 (accessed [today's date]).

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