Is AP1B1 p.Val709Met (c.2125G>A) pathogenic?

AP1B1 p.Val709Met (c.2125G>A) is classified Uncertain significance in AP1B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely benign (0.0871); Very rare (popmax 0.00445%, eas); Associated with Inborn genetic diseases.

What condition is associated with AP1B1 p.Val709Met (c.2125G>A)?

AP1B1 p.Val709Met (c.2125G>A) is associated with Inborn genetic diseases (ClinVar).

How common is AP1B1 p.Val709Met (c.2125G>A) in the general population?

AP1B1 p.Val709Met (c.2125G>A) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about AP1B1 p.Val709Met (c.2125G>A)?

AlphaMissense predicts likely benign (score 0.0871) — an in-silico prediction, not a clinical call.

AP1B1 p.Val709Met

c.2125G>A · VCV4114151

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0871 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0871	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -6.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 13 kb · p 0.0016 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00445% East Asian · 2/44,904 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000743% 12/1,614,034 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,452
Admixed American	0.00333%	30,005
European (non-Finnish)	0.000678%	147,505

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.Val709Met
Coding: c.2125G>A
MANE Select: NM_001127
Type: single nucleotide variant
Location: chr22:29339028 (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-val709met (accessed [today's date]).

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