Is AP1AR p.Leu12Val (c.34C>G) pathogenic?

AP1AR p.Leu12Val (c.34C>G) is classified Uncertain significance in AP1AR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-28). AlphaMissense: likely benign (0.086); Very rare (popmax 0.00405%, amr).

How common is AP1AR p.Leu12Val (c.34C>G) in the general population?

AP1AR p.Leu12Val (c.34C>G) is very rare (popmax 0.00405%, amr) (gnomAD).

What do computational predictors say about AP1AR p.Leu12Val (c.34C>G)?

AlphaMissense predicts likely benign (score 0.086) — an in-silico prediction, not a clinical call.

AP1AR p.Leu12Val

c.34C>G · VCV3921891

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.086 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00405%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.086	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -6.46	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 0.48	GERP 1.5, phastCons 0.14
Regional constraint	o/e 1.20	unconstrained · MANE · 35 kb · p 0.0024 · regional, not allelic
Overall
CADD	20.4	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 0.00405% Admixed American · 1/24,712 alleles

Filtering AF 3.3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.2e-05%

Overall 0.000696% 9/1,293,948 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0063%	15,884
Admixed Americangrpmax	0.00405%	24,712
South Asian	0.00259%	38,542
Finnishnot grpmax-eligible	0.00205%	48,674
African / African-American	0.00154%	65,098
European (non-Finnish)	0.000197%	506,465

Remaining individuals 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: AP1AR
Protein: p.Leu12Val
Coding: c.34C>G
MANE Select: NM_018569
Type: single nucleotide variant
Location: chr4:112232125 (GRCh38)
Gene constraint: LOEUF 1.048 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.16

Full AP1AR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP1AR p.Val284= Benign ★★ same type
AP1AR p.Arg114His Uncertain significance ★ ⚠ same type
AP1AR p.Arg123Gln Uncertain significance ★ ⚠ same type
AP1AR p.Arg14Gly Uncertain significance ★ ⚠ same type
AP1AR p.Arg302Gln Uncertain significance ★ ⚠ same type
AP1AR p.Asp86Glu Uncertain significance ★ ⚠ same type
AP1AR p.Asp86Gly Uncertain significance ★ ⚠ same type
AP1AR p.Gln21Arg Uncertain significance ★ ⚠ same type

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/ap1ar-p-leu12val (accessed [today's date]).

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