Is GP1BB p.Leu74Pro (c.221T>C) pathogenic?

GP1BB p.Leu74Pro (c.221T>C) is classified Uncertain significance in GP1BB (ClinVar, Single submitter, 1 submitter; last evaluated 2018-11-01). AlphaMissense: likely pathogenic (0.6588); No allele count reported in gnomAD v4.1 (AN 1,505,154).

How common is GP1BB p.Leu74Pro (c.221T>C) in the general population?

GP1BB p.Leu74Pro (c.221T>C) is no allele count reported in gnomAD v4.1 (AN 1,505,154) (gnomAD).

What do computational predictors say about GP1BB p.Leu74Pro (c.221T>C)?

AlphaMissense predicts likely pathogenic (score 0.6588) — an in-silico prediction, not a clinical call.

GP1BB p.Leu74Pro

c.221T>C · VCV4946932

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6588 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,505,154)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6588	likely pathogenic
REVEL	0.729	pathogenic-leaning
SaProt	LLR -7.71	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.1	GERP 1.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 891 bp · p 0.61 · regional, not allelic
Overall
CADD	29.1	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

No allele count reported in gnomAD v4.1 (AN 1,505,154). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: GP1BB
Protein: p.Leu74Pro
Coding: c.221T>C
MANE Select: NM_000407
Type: single nucleotide variant
Location: chr22:19724064 (GRCh38)
Gene constraint: LOEUF 1.922 · pLI 0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.43 · 3 PDB
Residue 74: a turn

Full GP1BB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GP1BB p.Leu74= Likely benign ★ same residue
GP1BB p.Asn89Asp Likely pathogenic ★★★ same type
GP1BB p.Asn89Thr Likely pathogenic ★★★ same type
GP1BB p.Cys141Ter Pathogenic ★★★ same type
GP1BB p.Cys147Ser Likely pathogenic ★★★ ⚠ same type
GP1BB p.Cys30Tyr Likely pathogenic ★★★ same type
GP1BB p.Cys32Ter Likely pathogenic ★★★ same type
GP1BB p.Glu136Ter 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/gp1bb-p-leu74pro (accessed [today's date]).

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