Is AP1B1 p.Arg235His (c.704G>A) pathogenic?

AP1B1 p.Arg235His (c.704G>A) is classified Likely benign in AP1B1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-04-04). AlphaMissense: ambiguous (0.4538); Very rare (popmax 0.00331%, nfe); Associated with AP1B1-related disorder.

What condition is associated with AP1B1 p.Arg235His (c.704G>A)?

AP1B1 p.Arg235His (c.704G>A) is associated with AP1B1-related disorder (ClinVar).

How common is AP1B1 p.Arg235His (c.704G>A) in the general population?

AP1B1 p.Arg235His (c.704G>A) is very rare (popmax 0.00331%, nfe) (gnomAD).

What do computational predictors say about AP1B1 p.Arg235His (c.704G>A)?

AlphaMissense predicts ambiguous (score 0.4538) — an in-silico prediction, not a clinical call.

AP1B1 p.Arg235His

c.704G>A · rs140871358 · VCV3036048

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4538 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00331%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

AP1B1-related disorder

Computational evidence

Protein change
AlphaMissense	0.4538	ambiguous
REVEL	0.256	benign-leaning
SaProt	LLR -11.75	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 18 kb · p 1.2e-17 · regional, not allelic
Overall
CADD	25.6	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 0.00331% European (non-Finnish) · 39/1,179,346 alleles

Filtering AF 0.00248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.011% 177/1,613,096 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.419%	239
Remaining individualsnot grpmax-eligible	0.0208%	4,804
European (non-Finnish)grpmax	0.00331%	30,240
East Asian	0.00223%	44,876

Ashkenazi Jewish 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: AP1B1
Protein: p.Arg235His
Coding: c.704G>A
MANE Select: NM_001127
dbSNP: rs140871358
Type: single nucleotide variant
Location: chr22:29356438 (GRCh38)
Gene constraint: LOEUF 0.476 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 20 PDB
Residue 235: an α-helix

Full AP1B1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

AP1B1-related disorder

Similar variants

AP1B1 p.Gly643Ser Uncertain significance ⚠ same condition
AP1B1 c.2164-8C>T Likely benign same condition
AP1B1 c.2309+8C>T Likely benign same condition
AP1B1 c.2524+5G>A Likely benign same condition
AP1B1 c.*7G>A Likely benign same condition
AP1B1 p.Ala373= Likely benign same condition
AP1B1 p.Ala609= Likely benign same condition
AP1B1 p.Ala87= Likely benign 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/ap1b1-p-arg235his (accessed [today's date]).

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