Is GPAM p.Lys757Arg (c.2270A>G) pathogenic?

GPAM p.Lys757Arg (c.2270A>G) is classified Uncertain significance in GPAM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-13). AlphaMissense: likely benign (0.0611); Ultra-rare (popmax 0.0764%, nfe).

How common is GPAM p.Lys757Arg (c.2270A>G) in the general population?

GPAM p.Lys757Arg (c.2270A>G) is ultra-rare (popmax 0.0764%, nfe) (gnomAD).

What do computational predictors say about GPAM p.Lys757Arg (c.2270A>G)?

AlphaMissense predicts likely benign (score 0.0611) — an in-silico prediction, not a clinical call.

GPAM p.Lys757Arg

c.2270A>G · rs150743685 · VCV2456272

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0611 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0764%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0611	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -6.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.053	GERP -0.74, phastCons 0.006
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 1.8e-05 · regional, not allelic
Overall
CADD	13.91	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0764% European (non-Finnish) · 899/1,177,224 alleles

Filtering AF 0.0722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0705%

Overall 0.0603% 972/1,611,022 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0764%	1,309
Remaining individualsnot grpmax-eligible	0.0481%	2,079
Admixed American	0.0416%	2,401
African / African-American	0.02%	4,998
Finnishnot grpmax-eligible	0.00312%	32,020
South Asian	0.0011%	91,006

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: GPAM
Protein: p.Lys757Arg
Coding: c.2270A>G
MANE Select: NM_001244949
dbSNP: rs150743685
Type: single nucleotide variant
Location: chr10:112155905 (GRCh38)
Gene constraint: LOEUF 0.747 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 2 PDB
Residue 757: an α-helix

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

Similar variants

GPAM p.Ala420Val Benign ★★ same type
GPAM p.Asp399= Benign ★★ same type
GPAM p.Ile43Val Benign ★★ same type
GPAM c.102+1G>A Uncertain significance ★ same type
GPAM p.Ala144Thr Uncertain significance ★ ⚠ same type
GPAM p.Ala144Val Uncertain significance ★ ⚠ same type
GPAM p.Ala327Thr Uncertain significance ★ ⚠ same type
GPAM p.Ala382Thr 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/gpam-p-lys757arg (accessed [today's date]).

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