Is AP1B1 p.Pro640Thr (c.1918C>A) pathogenic?

AP1B1 p.Pro640Thr (c.1918C>A) is classified Uncertain significance in AP1B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-20). AlphaMissense: likely benign (0.0586); Ultra-rare (popmax 0.036%, afr); Associated with Inborn genetic diseases.

What condition is associated with AP1B1 p.Pro640Thr (c.1918C>A)?

AP1B1 p.Pro640Thr (c.1918C>A) is associated with Inborn genetic diseases (ClinVar).

How common is AP1B1 p.Pro640Thr (c.1918C>A) in the general population?

AP1B1 p.Pro640Thr (c.1918C>A) is ultra-rare (popmax 0.036%, afr) (gnomAD).

What do computational predictors say about AP1B1 p.Pro640Thr (c.1918C>A)?

AlphaMissense predicts likely benign (score 0.0586) — an in-silico prediction, not a clinical call.

AP1B1 p.Pro640Thr

c.1918C>A · rs572161344 · VCV2526647

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0586 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.036%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0586	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -10.73	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 13 kb · p 0.0016 · regional, not allelic
Overall
CADD	23.7	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 0.036% African / African-American · 27/74,906 alleles

Filtering AF 0.0254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0219%

Overall 0.00226% 36/1,595,448 alleles · ultra-rare exomes 19/1,443,160 · genomes 17/152,288 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.036%	2,774
Remaining individualsnot grpmax-eligible	0.00323%	30,920
European (non-Finnish)	0.000597%	167,428

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.Pro640Thr
Coding: c.1918C>A
MANE Select: NM_001127
dbSNP: rs572161344
Type: single nucleotide variant
Location: chr22:29340736 (GRCh38)
Gene constraint: LOEUF 0.476 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 20 PDB

Full AP1B1 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

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AP1B1 p.Ala410Thr Uncertain significance ★ ⚠ same condition
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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-pro640thr (accessed [today's date]).

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