Is AP4M1 p.Ser222= (c.666C>T) pathogenic?

AP4M1 p.Ser222= (c.666C>T) is classified Likely benign in AP4M1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-09). Very rare (popmax 0.00801%, afr); Associated with hereditary spastic paraplegia 50.

What condition is associated with AP4M1 p.Ser222= (c.666C>T)?

AP4M1 p.Ser222= (c.666C>T) is associated with hereditary spastic paraplegia 50 (ClinVar).

How common is AP4M1 p.Ser222= (c.666C>T) in the general population?

AP4M1 p.Ser222= (c.666C>T) is very rare (popmax 0.00801%, afr) (gnomAD).

AP4M1 p.Ser222=

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.666C>T · rs140144409 · VCV2069190

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Conditions

hereditary spastic paraplegia 50

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -3.3
Overall
CADD	1.636	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00801% African / African-American · 6/74,916 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.00136% 22/1,614,016 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,486
Remaining individualsnot grpmax-eligible	0.0048%	20,830
East Asian	0.00223%	44,900
South Asian	0.0011%	91,082
European (non-Finnish)	0.000932%	107,274

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.Ser222=
Coding: c.666C>T
MANE Select: NM_004722
dbSNP: rs140144409
Type: single nucleotide variant
Location: chr7:100104933 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.16 · 6 PDB
Residue 222: 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 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
AP4M1 p.Gln183Ter 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-ser222 (accessed [today's date]).

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