Is AP1AR p.Phe10Leu (c.28T>C) pathogenic?

AP1AR p.Phe10Leu (c.28T>C) is classified Uncertain significance in AP1AR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely pathogenic (0.5901); Ultra-rare (popmax 0.0713%, eas).

How common is AP1AR p.Phe10Leu (c.28T>C) in the general population?

AP1AR p.Phe10Leu (c.28T>C) is ultra-rare (popmax 0.0713%, eas) (gnomAD).

What do computational predictors say about AP1AR p.Phe10Leu (c.28T>C)?

AlphaMissense predicts likely pathogenic (score 0.5901) — an in-silico prediction, not a clinical call.

AP1AR p.Phe10Leu

c.28T>C · rs543058773 · VCV2466296

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5901 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0713%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5901	likely pathogenic
REVEL	0.014	strongly benign-leaning
SaProt	LLR -5.78	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.5, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 35 kb · p 0.0024 · regional, not allelic
Overall
CADD	21.1	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 0.0713% East Asian · 23/32,266 alleles

Filtering AF 0.0487% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0413%

Overall 0.00884% 115/1,300,366 alleles · ultra-rare exomes 93/1,148,196 · genomes 22/152,170 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0713%	1,403
African / African-American	0.0231%	4,338
Admixed American	0.0201%	4,967
South Asian	0.0122%	8,186
Remaining individualsnot grpmax-eligible	0.00835%	11,976
European (non-Finnish)	0.0061%	16,389
Ashkenazi Jewishnot grpmax-eligible	0.00536%	18,670

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.Phe10Leu
Coding: c.28T>C
MANE Select: NM_018569
dbSNP: rs543058773
Type: single nucleotide variant
Location: chr4:112232119 (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.Phe10Cys 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-phe10leu (accessed [today's date]).

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