Is AP1G1 p.Met366Val (c.1096A>G) pathogenic?

AP1G1 p.Met366Val (c.1096A>G) is classified Uncertain significance in AP1G1 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-08-07). AlphaMissense: likely benign (0.2281); Ultra-rare (popmax 0.0158%, sas); Associated with Usmani-Riazuddin syndrome, autosomal recessive.

What condition is associated with AP1G1 p.Met366Val (c.1096A>G)?

AP1G1 p.Met366Val (c.1096A>G) is associated with Usmani-Riazuddin syndrome, autosomal recessive (ClinVar).

How common is AP1G1 p.Met366Val (c.1096A>G) in the general population?

AP1G1 p.Met366Val (c.1096A>G) is ultra-rare (popmax 0.0158%, sas) (gnomAD).

What do computational predictors say about AP1G1 p.Met366Val (c.1096A>G)?

AlphaMissense predicts likely benign (score 0.2281) — an in-silico prediction, not a clinical call.

AP1G1 p.Met366Val

c.1096A>G · rs770797451 · VCV1299371

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2281 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0158%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Usmani-Riazuddin syndrome, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.2281	likely benign
REVEL	0.279	benign-leaning
SaProt	LLR -9.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.28	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 6.2	GERP 1.1, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 33 kb · p 3.2e-16 · regional, not allelic
Overall
CADD	26.9	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 0.0158% South Asian · 14/88,384 alleles

Filtering AF 0.00956% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00766%

Overall 0.00112% 18/1,603,182 alleles · ultra-rare exomes 18/1,450,940 · genomes 0/152,242 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0158%	6,313
Ashkenazi Jewishnot grpmax-eligible	0.00343%	29,172
Remaining individualsnot grpmax-eligible	0.00161%	62,094
European (non-Finnish)	0.00017%	588,582

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: AP1G1
Protein: p.Met366Val
Coding: c.1096A>G
MANE Select: NM_001128
dbSNP: rs770797451
Type: single nucleotide variant
Location: chr16:71756152 (GRCh38)
Gene constraint: LOEUF 0.113 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.56 · 1 PDB
Residue 366: a UniProt-annotated variant site (in usrisr; does not fully rescue morphological defects in a zebrafish animal model; affects trafficking of transferrin from recycling endosomes to plasma membrane; no effect on subcellular location in the perinuclear region; does not affect interaction with ap-1 complex subunits ap1b1, ap1m1 and ap1s1)

Full AP1G1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Usmani-Riazuddin syndrome, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AP1G1 c.1497+1G>A Pathogenic ★ same condition
AP1G1 p.Thr601Arg Uncertain significance ★ ⚠ same condition
AP1G1 p.Pro243His Pathogenic same condition
AP1G1 p.Met172fs Pathogenic ★ same condition
AP1G1 p.Tyr290fs Likely pathogenic ★ same condition
AP1G1 p.Arg15Trp Likely pathogenic ★★ same type
AP1G1 p.Arg416Ter Pathogenic ★★ same type
AP1G1 p.Arg46Ter 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/ap1g1-p-met366val (accessed [today's date]).

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