Is AP4M1 p.Cys319Arg (c.955T>C) pathogenic?

AP4M1 p.Cys319Arg (c.955T>C) is classified Pathogenic/Likely pathogenic in AP4M1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-11-20). AlphaMissense: likely pathogenic (0.9937); Very rare (popmax 0.00549%, sas); Associated with Inborn genetic diseases.

What condition is associated with AP4M1 p.Cys319Arg (c.955T>C)?

AP4M1 p.Cys319Arg (c.955T>C) is associated with Inborn genetic diseases, hereditary spastic paraplegia 50 (ClinVar).

How common is AP4M1 p.Cys319Arg (c.955T>C) in the general population?

AP4M1 p.Cys319Arg (c.955T>C) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about AP4M1 p.Cys319Arg (c.955T>C)?

AlphaMissense predicts likely pathogenic (score 0.9937) — an in-silico prediction, not a clinical call.

AP4M1 p.Cys319Arg

c.955T>C · rs754498075 · VCV210216

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9937 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9937	likely pathogenic ✓ concordant with ClinVar · top 2% in AP4M1
REVEL	0.483	indeterminate
SaProt	LLR -16.86	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 5,164 bp · p 0.093 · regional, not allelic
Overall
CADD	25.4	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 0.00549% South Asian · 5/91,084 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000929% 15/1,614,028 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,217
East Asian	0.00446%	22,443
African / African-American	0.004%	24,977
Remaining individualsnot grpmax-eligible	0.0016%	62,484
Finnishnot grpmax-eligible	0.00156%	64,018
European (non-Finnish)	0.000254%	393,346

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.Cys319Arg
Coding: c.955T>C
MANE Select: NM_004722
dbSNP: rs754498075
Type: single nucleotide variant
Location: chr7:100105984 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.16 · 6 PDB
Residue 319: the mhd domain; a β-strand

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.Cys319Tyr Likely pathogenic ★ same residue
AP4M1 p.Cys319Phe 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-cys319arg (accessed [today's date]).

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