Is GP6 p.Ser250Arg (c.748A>C) pathogenic?

GP6 p.Ser250Arg (c.748A>C) is classified Conflicting classifications of pathogenicity in GP6 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-21). AlphaMissense: likely benign (0.2059); Rare (popmax 0.386%, sas).

How common is GP6 p.Ser250Arg (c.748A>C) in the general population?

GP6 p.Ser250Arg (c.748A>C) is rare (popmax 0.386%, sas) (gnomAD).

What do computational predictors say about GP6 p.Ser250Arg (c.748A>C)?

AlphaMissense predicts likely benign (score 0.2059) — an in-silico prediction, not a clinical call.

GP6 p.Ser250Arg

c.748A>C · rs202044825 · VCV737240

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2059 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.386%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2059	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -7.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.24	GERP -1.1
Overall
CADD	17.03	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 0.386% South Asian · 349/90,506 alleles

Filtering AF 0.352% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.339%

Overall 0.0254% 402/1,583,646 alleles · rare exomes 379/1,431,398 · genomes 23/152,248 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.386%	259
Middle Eastern	0.216%	462
Remaining individualsnot grpmax-eligible	0.0244%	4,097
Admixed American	0.00333%	29,988
East Asian	0.00224%	44,726
European (non-Finnish)	0.00191%	52,363

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.Ser250Arg
Coding: c.748A>C
MANE Select: NM_016363
dbSNP: rs202044825
Type: single nucleotide variant
Location: chr19:55015710 (GRCh38)
Gene constraint: LOEUF 1.734 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.52 · 6 PDB

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

Similar variants

GP6 p.Trp160Ter Pathogenic ★★ same type
GP6 c.*106A>C Uncertain significance ★★ same type
GP6 c.*189C>T Uncertain significance ★★ same type
GP6 c.*304C>T Uncertain significance ★★ same type
GP6 c.*523G>C Uncertain significance ★★ same type
GP6 c.*531T>C Uncertain significance ★★ same type
GP6 c.*820T>C Uncertain significance ★★ same type
GP6 p.Arg262Cys Uncertain significance ★★ ⚠ 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/gp6-p-ser250arg (accessed [today's date]).

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