Is GPAM p.Pro417Leu (c.1250C>T) pathogenic?

GPAM p.Pro417Leu (c.1250C>T) is classified Uncertain significance in GPAM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: likely benign (0.1262); Very rare (popmax 0.00938%, afr).

How common is GPAM p.Pro417Leu (c.1250C>T) in the general population?

GPAM p.Pro417Leu (c.1250C>T) is very rare (popmax 0.00938%, afr) (gnomAD).

What do computational predictors say about GPAM p.Pro417Leu (c.1250C>T)?

AlphaMissense predicts likely benign (score 0.1262) — an in-silico prediction, not a clinical call.

GPAM p.Pro417Leu

c.1250C>T · VCV4672804

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1262 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00938%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1262	likely benign
REVEL	0.109	moderately benign-leaning
SaProt	LLR -12.02	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 0.37, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 1.8e-05 · regional, not allelic
Overall
CADD	21.4	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 0.00938% African / African-American · 7/74,640 alleles

Filtering AF 0.00439% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00268% 43/1,604,872 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00938%	10,663
East Asian	0.0067%	14,936
European (non-Finnish)	0.00256%	39,061
Remaining individualsnot grpmax-eligible	0.00161%	62,176
Finnishnot grpmax-eligible	0.00156%	64,002
South Asian	0.0011%	90,928

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.Pro417Leu
Coding: c.1250C>T
MANE Select: NM_001244949
Type: single nucleotide variant
Location: chr10:112164582 (GRCh38)
Gene constraint: LOEUF 0.747 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 2 PDB

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-pro417leu (accessed [today's date]).

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