Is AP4M1 p.Asp288His (c.862G>C) pathogenic?

AP4M1 p.Asp288His (c.862G>C) is classified Uncertain significance in AP4M1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-02). AlphaMissense: likely pathogenic (0.5657); Very rare (popmax 0.000124%); Associated with hereditary spastic paraplegia 50.

What condition is associated with AP4M1 p.Asp288His (c.862G>C)?

AP4M1 p.Asp288His (c.862G>C) is associated with hereditary spastic paraplegia 50 (ClinVar).

How common is AP4M1 p.Asp288His (c.862G>C) in the general population?

AP4M1 p.Asp288His (c.862G>C) is very rare (popmax 0.000124%) (gnomAD).

What do computational predictors say about AP4M1 p.Asp288His (c.862G>C)?

AlphaMissense predicts likely pathogenic (score 0.5657) — an in-silico prediction, not a clinical call.

AP4M1 p.Asp288His

Q: How is Severe intellectual disability and progressive spastic paraplegia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.862G>C · rs767611212 · VCV1517947

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5657 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000124%)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 50

Computational evidence

Protein change
AlphaMissense	0.5657	likely pathogenic
REVEL	0.269	benign-leaning
SaProt	LLR -6.05	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 5,164 bp · p 0.093 · regional, not allelic
Overall
CADD	33.0	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

Grpmax group 0.000124%

Overall 0.000124% 2/1,613,876 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: AP4M1
Protein: p.Asp288His
Coding: c.862G>C
MANE Select: NM_004722
dbSNP: rs767611212
Type: single nucleotide variant
Location: chr7:100105472 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.16 · 6 PDB
Residue 288: the mhd domain

Full AP4M1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 50 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Severe intellectual disability and progressive spastic paraplegia (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

AP4M1 p.Asp288= Likely benign ★ same residue
AP4M1 p.Asp288fs Pathogenic ★ same residue
AP4M1 p.Asp288Asn Uncertain significance ★★ ⚠ same residue
AP4M1 c.1137+1G>T Pathogenic/Likely pathogenic ★★ same condition
AP4M1 c.930-1G>C Likely pathogenic ★★ same condition
AP4M1 p.Arg268Ter Pathogenic ★★ same condition
AP4M1 p.Arg306Ter Pathogenic ★★ same condition
AP4M1 p.Arg318Ter Pathogenic ★★ same condition

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/ap4m1-p-asp288his (accessed [today's date]).

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