Is AP1AR p.Tyr165Cys (c.494A>G) pathogenic?

AP1AR p.Tyr165Cys (c.494A>G) is classified Uncertain significance in AP1AR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-29). AlphaMissense: likely benign (0.0885); Ultra-rare (popmax 0.0243%, sas).

How common is AP1AR p.Tyr165Cys (c.494A>G) in the general population?

AP1AR p.Tyr165Cys (c.494A>G) is ultra-rare (popmax 0.0243%, sas) (gnomAD).

What do computational predictors say about AP1AR p.Tyr165Cys (c.494A>G)?

AlphaMissense predicts likely benign (score 0.0885) — an in-silico prediction, not a clinical call.

AP1AR p.Tyr165Cys

c.494A>G · VCV3300164

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0885 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0243%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0885	likely benign
REVEL	0.205	benign-leaning
SaProt	LLR -7.02	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 8.1	GERP 1.7, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 35 kb · p 0.0024 · regional, not allelic
Overall
CADD	22.6	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 0.0243% South Asian · 22/90,638 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.0018% 29/1,609,498 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0243%	4,120
African / African-American	0.00401%	24,955
Remaining individualsnot grpmax-eligible	0.00321%	31,138
Admixed American	0.00168%	59,634
European (non-Finnish)	8.49e-05%	1,177,350

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.Tyr165Cys
Coding: c.494A>G
MANE Select: NM_018569
Type: single nucleotide variant
Location: chr4:112265787 (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.Tyr165His Uncertain significance ★ ⚠ same residue
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

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-tyr165cys (accessed [today's date]).

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