Is AP4M1 p.Glu111Asp (c.333A>C) pathogenic?

AP4M1 p.Glu111Asp (c.333A>C) is classified Conflicting classifications of pathogenicity in AP4M1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-11-17). AlphaMissense: likely pathogenic (0.9863); Ultra-rare (popmax 0.0613%, nfe); Associated with hereditary spastic paraplegia 50.

What condition is associated with AP4M1 p.Glu111Asp (c.333A>C)?

AP4M1 p.Glu111Asp (c.333A>C) is associated with hereditary spastic paraplegia 50 (ClinVar).

How common is AP4M1 p.Glu111Asp (c.333A>C) in the general population?

AP4M1 p.Glu111Asp (c.333A>C) is ultra-rare (popmax 0.0613%, nfe) (gnomAD).

What do computational predictors say about AP4M1 p.Glu111Asp (c.333A>C)?

AlphaMissense predicts likely pathogenic (score 0.9863) — an in-silico prediction, not a clinical call.

AP4M1 p.Glu111Asp

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.333A>C · rs138437966 · VCV210212

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9863 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0613%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 50

Computational evidence

Protein change
AlphaMissense	0.9863	likely pathogenic · top 5% in AP4M1
REVEL	0.741	pathogenic-leaning
SaProt	LLR -12.39	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 0.49	GERP -4.2, phastCons 0.84
Regional constraint	o/e 1.07	unconstrained · MANE · 5,164 bp · p 0.093 · regional, not allelic
Overall
CADD	21.7	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 0.0613% European (non-Finnish) · 723/1,179,864 alleles

Filtering AF 0.0575% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.056%

Overall 0.0568% 916/1,613,266 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.21%	83
Ashkenazi Jewishnot grpmax-eligible	0.314%	318
Remaining individualsnot grpmax-eligible	0.0768%	1,302
European (non-Finnish)grpmax	0.0613%	1,632
Admixed American	0.0534%	1,873
African / African-American	0.00669%	14,937
Finnishnot grpmax-eligible	0.00626%	15,964

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Glu111Asp
Coding: c.333A>C
MANE Select: NM_004722
dbSNP: rs138437966
Type: single nucleotide variant
Location: chr7:100102942 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.16 · 6 PDB

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.Glu111Lys Uncertain significance ★★ ⚠ same residue
AP4M1 p.Glu111Gln 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
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-glu111asp (accessed [today's date]).

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