Is GP6 p.Phe165= (c.495T>C) pathogenic?

GP6 p.Phe165= (c.495T>C) is classified Benign in GP6 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 81.9%, amr) — too common for a highly-penetrant pathogenic allele; Associated with platelet-type bleeding disorder 11.

What condition is associated with GP6 p.Phe165= (c.495T>C)?

GP6 p.Phe165= (c.495T>C) is associated with platelet-type bleeding disorder 11 (ClinVar).

GP6 p.Phe165=

Q: How common is GP6 p.Phe165= (c.495T>C) in the general population?

GP6 p.Phe165= (c.495T>C) is common (popmax 81.9%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.495T>C · rs892089 · VCV257419

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 81.9%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

platelet-type bleeding disorder 11

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 1.2	GERP -3.5, phastCons 0.98
Overall
CADD	4.919	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 81.9% Admixed American · 49,135/60,008 alleles

Filtering AF 81.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 81.6%

Overall 80.2% 1,292,814/1,611,254 alleles · common exomes 1,177,329/1,459,134 · genomes 115,485/152,120 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	87%	1
Admixed Americangrpmax	81.9%	1
European (non-Finnish)	81.8%	1
East Asian	80.8%	1
Remaining individualsnot grpmax-eligible	79.6%	1
Middle Eastern	78.4%	1
Ashkenazi Jewishnot grpmax-eligible	78.2%	1
Amishnot grpmax-eligible	77%	1
South Asian	72.9%	1
African / African-American	59.4%	2

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: GP6
Protein: p.Phe165=
Coding: c.495T>C
MANE Select: NM_016363
dbSNP: rs892089
Type: single nucleotide variant
Location: chr19:55027693 (GRCh38)
Gene constraint: LOEUF 1.734 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.52 · 6 PDB
Residue 165: a β-strand; the ig-like c2-type 2 domain

Full GP6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

platelet-type bleeding disorder 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GP6 c.*395C>T Benign ★★ same condition
GP6 c.*485C>T Likely benign ★★ same condition
GP6 c.*693A>G Benign ★★ same condition
GP6 c.*792T>C Benign ★★ same condition
GP6 p.Ala249Thr Benign ★★ same condition
GP6 p.Arg162= Benign ★★ same condition
GP6 p.Glu237Lys Benign ★★ same condition
GP6 p.Leu312= Benign ★★ 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/gp6-p-phe165 (accessed [today's date]).

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