Is APOLD1 p.Arg18Trp (c.52C>T) pathogenic?

APOLD1 p.Arg18Trp (c.52C>T) is classified Uncertain significance in APOLD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-09). AlphaMissense: likely benign (0.1919); Ultra-rare (popmax 0.0183%, nfe).

How common is APOLD1 p.Arg18Trp (c.52C>T) in the general population?

APOLD1 p.Arg18Trp (c.52C>T) is ultra-rare (popmax 0.0183%, nfe) (gnomAD).

What do computational predictors say about APOLD1 p.Arg18Trp (c.52C>T)?

AlphaMissense predicts likely benign (score 0.1919) — an in-silico prediction, not a clinical call.

APOLD1 p.Arg18Trp

c.52C>T · rs757476941 · VCV2376354

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1919 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1919	likely benign
REVEL	0.167	moderately benign-leaning
SaProt	LLR -9.41	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 3.1	GERP -0.63, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 1,957 bp · p 0.031 · regional, not allelic
Overall
CADD	23.8	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R49W vs ClinVar R18W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0183% European (non-Finnish) · 204/1,114,912 alleles

Filtering AF 0.0162% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.0146% 213/1,459,370 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0183%	5,465
Remaining individualsnot grpmax-eligible	0.00888%	11,267
Admixed American	0.00796%	12,565
African / African-American	0.00148%	67,588

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: APOLD1
Protein: p.Arg18Trp
Coding: c.52C>T
MANE Select: NM_030817
dbSNP: rs757476941
Type: single nucleotide variant
Location: chr12:12786957 (GRCh38)
Gene constraint: LOEUF 1.959 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.17

Full APOLD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APOLD1 p.Ala159Val Uncertain significance ★ ⚠ same type
APOLD1 p.Ala244Thr Uncertain significance ★ ⚠ same type
APOLD1 p.Ala42Pro Uncertain significance ★ ⚠ same type
APOLD1 p.Ala67Ser Uncertain significance ★ ⚠ same type
APOLD1 p.Arg132Leu Uncertain significance ★ ⚠ same type
APOLD1 p.Arg150Leu Uncertain significance ★ ⚠ same type
APOLD1 p.Arg150Ser Uncertain significance ★ ⚠ same type
APOLD1 p.Arg157Lys 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/apold1-p-arg18trp (accessed [today's date]).

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