Is AP4B1 p.Arg169Cys (c.505C>T) pathogenic?

AP4B1 p.Arg169Cys (c.505C>T) is classified Uncertain significance in AP4B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely pathogenic (0.7977); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with AP4B1 p.Arg169Cys (c.505C>T)?

AP4B1 p.Arg169Cys (c.505C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AP4B1 p.Arg169Cys (c.505C>T) in the general population?

AP4B1 p.Arg169Cys (c.505C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about AP4B1 p.Arg169Cys (c.505C>T)?

AlphaMissense predicts likely pathogenic (score 0.7977) — an in-silico prediction, not a clinical call.

AP4B1 p.Arg169Cys

c.505C>T · VCV4115711

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7977	likely pathogenic
REVEL	0.26	benign-leaning
SaProt	LLR -9.39	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.23	acceptor loss · deltas
Pangolin	Δ0.21	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 9,649 bp · p 0.84 · regional, not allelic
Overall
CADD	32.0	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 0.00134% African / African-American · 1/74,880 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,866 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,880
European (non-Finnish)	0.000339%	294,985

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: AP4B1
Protein: p.Arg169Cys
Coding: c.505C>T
MANE Select: NM_001253852
Type: single nucleotide variant
Location: chr1:113901348 (GRCh38)
Gene constraint: LOEUF 0.777 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.56 · 5 PDB

Full AP4B1 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

Similar variants

AP4B1 p.Arg169His Uncertain significance ★★ ⚠ same residue
AP4B1 p.Arg169Ser Uncertain significance ★★ ⚠ same residue
AP4B1 c.114-2A>G Pathogenic ★★ same condition
AP4B1 c.470-6T>G Uncertain significance ★★ same condition
AP4B1 p.Ala361Val Uncertain significance ★★ ⚠ same condition
AP4B1 p.Ala83Pro Uncertain significance ★★ ⚠ same condition
AP4B1 p.Arg130Gln Uncertain significance ★★ ⚠ same condition
AP4B1 p.Arg224Cys Uncertain significance ★★ ⚠ 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/ap4b1-p-arg169cys (accessed [today's date]).

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