Is APOLD1 p.Ala159Val (c.476C>T) pathogenic?

APOLD1 p.Ala159Val (c.476C>T) is classified Uncertain significance in APOLD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-04). AlphaMissense: likely benign (0.311); Ultra-rare (popmax 0.019%, nfe).

How common is APOLD1 p.Ala159Val (c.476C>T) in the general population?

APOLD1 p.Ala159Val (c.476C>T) is ultra-rare (popmax 0.019%, nfe) (gnomAD).

What do computational predictors say about APOLD1 p.Ala159Val (c.476C>T)?

AlphaMissense predicts likely benign (score 0.311) — an in-silico prediction, not a clinical call.

APOLD1 p.Ala159Val

c.476C>T · rs145235534 · VCV2357027

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.311 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.019%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.311	likely benign
REVEL	0.175	moderately benign-leaning
SaProt	LLR -5.34	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 7.3	GERP 2.6, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 1,957 bp · p 0.031 · regional, not allelic
Overall
CADD	26.4	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A190V vs ClinVar A159V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.019% European (non-Finnish) · 224/1,180,048 alleles

Filtering AF 0.0169% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0162%

Overall 0.0229% 370/1,614,052 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.432%	231
Remaining individualsnot grpmax-eligible	0.0256%	3,906
European (non-Finnish)grpmax	0.019%	5,268
Admixed American	0.00167%	60,016
African / African-American	0.00133%	74,946

Ashkenazi Jewish 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: APOLD1
Protein: p.Ala159Val
Coding: c.476C>T
MANE Select: NM_030817
dbSNP: rs145235534
Type: single nucleotide variant
Location: chr12:12787381 (GRCh38)
Gene constraint: LOEUF 1.959 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.17
Residue 159: a UniProt-annotated variant site (in bdvas; likely pathogenic)

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

Similar variants

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
APOLD1 p.Arg18Trp 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-ala159val (accessed [today's date]).

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