Is AP1G1 p.Pro243His (c.728C>A) pathogenic?

AP1G1 p.Pro243His (c.728C>A) is classified Pathogenic in AP1G1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-10-04). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1; Associated with Usmani-Riazuddin syndrome, autosomal recessive.

What condition is associated with AP1G1 p.Pro243His (c.728C>A)?

AP1G1 p.Pro243His (c.728C>A) is associated with Usmani-Riazuddin syndrome, autosomal recessive (ClinVar).

How common is AP1G1 p.Pro243His (c.728C>A) in the general population?

AP1G1 p.Pro243His (c.728C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AP1G1 p.Pro243His (c.728C>A)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

AP1G1 p.Pro243His

c.728C>A · rs2145472327 · VCV1299370

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Usmani-Riazuddin syndrome, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic ✓ concordant with ClinVar · top 3% in AP1G1
REVEL	0.678	pathogenic-leaning
SaProt	LLR -17.27	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 33 kb · p 3.2e-16 · regional, not allelic
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AP1G1
Protein: p.Pro243His
Coding: c.728C>A
MANE Select: NM_001128
dbSNP: rs2145472327
Type: single nucleotide variant
Location: chr16:71765499 (GRCh38)
Gene constraint: LOEUF 0.113 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.56 · 1 PDB
Residue 243: a UniProt-annotated variant site (in usrisr; does not fully rescue morphological defects in a zebrafish animal model; affects trafficking of transferrin from early to recycling endosomes; 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.Met366Val Uncertain significance ★ ⚠ same condition
AP1G1 p.Thr601Arg Uncertain significance ★ ⚠ 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-pro243his (accessed [today's date]).

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