Is AP4M1 p.Arg362His (c.1085G>A) pathogenic?

AP4M1 p.Arg362His (c.1085G>A) is classified Uncertain significance in AP4M1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-22). AlphaMissense: likely benign (0.0667); Ultra-rare (popmax 0.0329%, mid); Associated with hereditary spastic paraplegia 50.

What condition is associated with AP4M1 p.Arg362His (c.1085G>A)?

AP4M1 p.Arg362His (c.1085G>A) is associated with hereditary spastic paraplegia 50 (ClinVar).

How common is AP4M1 p.Arg362His (c.1085G>A) in the general population?

AP4M1 p.Arg362His (c.1085G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about AP4M1 p.Arg362His (c.1085G>A)?

AlphaMissense predicts likely benign (score 0.0667) — an in-silico prediction, not a clinical call.

AP4M1 p.Arg362His

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.1085G>A · rs764352275 · VCV2171072

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0667 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 50

Computational evidence

Protein change
AlphaMissense	0.0667	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -6.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.4	GERP -3.5
Regional constraint	o/e 1.07	unconstrained · MANE · 5,164 bp · p 0.093 · regional, not allelic
Overall
CADD	2.17	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00217% 35/1,613,694 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
Remaining individualsnot grpmax-eligible	0.0048%	20,827
African / African-American	0.004%	24,973
South Asian	0.00329%	30,363
East Asian	0.00223%	44,892
European (non-Finnish)	0.00195%	51,306

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.Arg362His
Coding: c.1085G>A
MANE Select: NM_004722
dbSNP: rs764352275
Type: single nucleotide variant
Location: chr7:100106462 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.16 · 6 PDB
Residue 362: the mhd domain; a β-strand

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.Arg362Cys Uncertain significance ★ ⚠ same residue
AP4M1 p.Arg362= Likely benign ★ 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
AP4M1 p.Arg338Ter Pathogenic/Likely 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-arg362his (accessed [today's date]).

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