Is GPAM p.Ile43Val (c.127A>G) pathogenic?

GPAM p.Ile43Val (c.127A>G) is classified Benign in GPAM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-01-10). AlphaMissense: likely benign (0.0521); Common (popmax 93.1%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about GPAM p.Ile43Val (c.127A>G)?

AlphaMissense predicts likely benign (score 0.0521) — an in-silico prediction, not a clinical call.

GPAM p.Ile43Val

Q: How common is GPAM p.Ile43Val (c.127A>G) in the general population?

GPAM p.Ile43Val (c.127A>G) is common (popmax 93.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.127A>G · rs2792751 · VCV1285804

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0521 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 93.1%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0521	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -5.96	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 1.9	GERP -1.9, phastCons 0.89
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 1.8e-05 · regional, not allelic
Overall
CADD	1.418	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 93.1% African / African-American · 69,787/74,926 alleles

Filtering AF 92.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 92.3%

Overall 73.3% 1,178,582/1,608,874 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	93.1%	1
South Asian	81.7%	1
East Asian	75.1%	1
Remaining individualsnot grpmax-eligible	73.4%	1
European (non-Finnish)	72.1%	1
Admixed American	71.6%	1
Finnishnot grpmax-eligible	67.6%	1
Middle Eastern	67.4%	1
Ashkenazi Jewishnot grpmax-eligible	57.2%	2
Amishnot grpmax-eligible	57.1%	2

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.Ile43Val
Coding: c.127A>G
MANE Select: NM_001244949
dbSNP: rs2792751
Type: single nucleotide variant
Location: chr10:112180571 (GRCh38)
Gene constraint: LOEUF 0.747 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 2 PDB
Residue 43: a UniProt-annotated variant site (in)

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 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
GPAM p.Ala401Thr 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-ile43val (accessed [today's date]).

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