Is AP1G2 p.Leu373Val (c.1117C>G) pathogenic?

AP1G2 p.Leu373Val (c.1117C>G) is classified Uncertain significance in AP1G2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-20). AlphaMissense: likely benign (0.3147); Very rare (popmax 0.000254%, nfe).

How common is AP1G2 p.Leu373Val (c.1117C>G) in the general population?

AP1G2 p.Leu373Val (c.1117C>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about AP1G2 p.Leu373Val (c.1117C>G)?

AlphaMissense predicts likely benign (score 0.3147) — an in-silico prediction, not a clinical call.

AP1G2 p.Leu373Val

c.1117C>G · VCV3922092

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3147 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3147	likely benign
REVEL	0.417	indeterminate
SaProt	LLR -13.35	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.21	acceptor loss, 11 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 5.1	GERP 1.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 7,562 bp · p 0.22 · regional, not allelic
Overall
CADD	23.3	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 0.000254% European (non-Finnish) · 3/1,179,992 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,746 alleles · very rare

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: AP1G2
Protein: p.Leu373Val
Coding: c.1117C>G
MANE Select: NM_003917
Type: single nucleotide variant
Location: chr14:23563831 (GRCh38)
Gene constraint: LOEUF 1.004 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.13 · 4 PDB
Residue 373: the 'essential for ubiquitin-binding' region

Full AP1G2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP1G2 p.Leu373Pro Uncertain significance ★ ⚠ same residue
AP1G2 p.Ala181Pro Uncertain significance ★ ⚠ same type
AP1G2 p.Ala360Thr Uncertain significance ★ ⚠ same type
AP1G2 p.Ala430Val Uncertain significance ★ ⚠ same type
AP1G2 p.Ala465Glu Uncertain significance ★ ⚠ same type
AP1G2 p.Ala508Thr Uncertain significance ★ ⚠ same type
AP1G2 p.Ala527Val Uncertain significance ★ ⚠ same type
AP1G2 p.Ala76Thr 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/ap1g2-p-leu373val (accessed [today's date]).

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