Is GP9 p.Phe71Cys (c.212T>G) pathogenic?

GP9 p.Phe71Cys (c.212T>G) is classified Likely pathogenic in GP9 (ClinVar, Expert panel, 4 submitters; last evaluated 2026-01-20). AlphaMissense: likely pathogenic (0.9774); Very rare (popmax 8.48e-05%, nfe); Associated with Bernard-Soulier syndrome.

What condition is associated with GP9 p.Phe71Cys (c.212T>G)?

GP9 p.Phe71Cys (c.212T>G) is associated with Bernard-Soulier syndrome (ClinVar).

How common is GP9 p.Phe71Cys (c.212T>G) in the general population?

GP9 p.Phe71Cys (c.212T>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Bernard-Soulier syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about GP9 p.Phe71Cys (c.212T>G)?

AlphaMissense predicts likely pathogenic (score 0.9774) — an in-silico prediction, not a clinical call.

GP9 p.Phe71Cys

c.212T>G · rs121918037 · VCV1491487

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9774 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Bernard-Soulier syndrome

ClinGen expert panel — Platelet Disorders VCEP

Likely Pathogenic for Bernard-Soulier syndrome. Applied ACMG criteria (verbatim):

PM2_Supporting PM3_Strong PP4

Curation rationale (ClinGen, verbatim)

The c.212T>G variant in GP9 is a missense variant predicted to cause substitution of Phenylalanine by Cysteine at amino acid 71 (p.Phe71Cys). At least one patient (Patient BS-23 in PMID:21699652) with this variant had aggregation absent for ristocetin and present for all other agonists, as well as less than 10% expression of GPIba measured by flow cytometry, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding which is consistent with Bernard-Soulier syndrome (PP4). This variant has been detected in at least three unrelated probands with Bernard-Soulier syndrome. Two of these individuals were homozygous for the variant (PMID:21699652, 1 PM3 point). One individual was compound heterozygous for this variant and the NM_000174.5(GP9):c.182A>G (p.Asn61Ser) which has been classified as Pathogenic by the PD VCEP. (1 PM3 point). These variants were confirmed in trans by family testing (2 PM3 points, PM3_Strong). The Grpmax filtering allele frequency in gnomaDv4.1 is 0 (based on 1/1179890 alleles) in the European (non-Finnish) population, which is below the <0.0000329 threshold for PM2_supporting. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4, PM3, PM2_Supporting, PM3_Strong (VCEP specifications version 1).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9774	likely pathogenic ✓ concordant with ClinVar · top 1% in GP9
REVEL	0.623	indeterminate
SaProt	LLR -12.67	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 530 bp · p 0.38 · regional, not allelic
Overall
CADD	24.3	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 8.48e-05% European (non-Finnish) · 1/1,179,890 alleles

Overall 6.2e-05% 1/1,613,888 alleles · very rare exomes 1/1,461,534 · genomes 0/152,354 · 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: GP9
Protein: p.Phe71Cys
Coding: c.212T>G
MANE Select: NM_000174
dbSNP: rs121918037
Type: single nucleotide variant
Location: chr3:129061951 (GRCh38)
Structure: AlphaFold pLDDT 84.43 · 2 PDB
Residue 71: a UniProt-annotated variant site (in bss); a turn

Full GP9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Bernard-Soulier syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Bernard-Soulier syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

GP9 p.Phe71Ser Pathogenic ★★★ same residue
GP9 p.Asn61Ser Pathogenic ★★★ same condition
GP9 p.Cys135Tyr Likely pathogenic ★★★ ⚠ same condition
GP9 p.Cys24Arg Likely pathogenic ★★★ same condition
GP9 p.Cys38Arg Likely pathogenic ★★★ same condition
GP9 p.Cys89Tyr Pathogenic ★★★ same condition
GP9 p.Leu56Pro Likely pathogenic ★★★ same condition
GP9 p.Leu7Pro Likely pathogenic ★★★ ⚠ 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/gp9-p-phe71cys (accessed [today's date]).

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