Is AP4M1 p.Asp43Glu (c.129C>A) pathogenic?

AP4M1 p.Asp43Glu (c.129C>A) is classified Uncertain significance in AP4M1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-07). AlphaMissense: likely benign (0.1082); Very rare (popmax 0.00449%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AP4M1 p.Asp43Glu (c.129C>A)?

AP4M1 p.Asp43Glu (c.129C>A) is associated with Inborn genetic diseases, hereditary spastic paraplegia 50 (ClinVar).

How common is AP4M1 p.Asp43Glu (c.129C>A) in the general population?

AP4M1 p.Asp43Glu (c.129C>A) is very rare (popmax 0.00449%, nfe) (gnomAD).

What do computational predictors say about AP4M1 p.Asp43Glu (c.129C>A)?

AlphaMissense predicts likely benign (score 0.1082) — an in-silico prediction, not a clinical call.

AP4M1 p.Asp43Glu

c.129C>A · rs760835879 · VCV471065

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1082 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00449%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1082	likely benign
REVEL	0.291	indeterminate
SaProt	LLR -5.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.44	GERP -4.2, phastCons 0.034
Regional constraint	o/e 1.07	unconstrained · MANE · 5,164 bp · p 0.093 · regional, not allelic
Overall
CADD	16.28	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 0.00449% European (non-Finnish) · 53/1,179,962 alleles

Filtering AF 0.0035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00318%

Overall 0.00347% 56/1,613,092 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,820
European (non-Finnish)grpmax	0.00449%	22,263

Remaining individuals 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.Asp43Glu
Coding: c.129C>A
MANE Select: NM_004722
dbSNP: rs760835879
Type: single nucleotide variant
Location: chr7:100101950 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia 50

Similar variants

AP4M1 p.Asp43fs Pathogenic ★ 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
AP4M1 p.Cys319Arg 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-asp43glu (accessed [today's date]).

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