Is APOLD1 p.Ser191Arg (c.571A>C) pathogenic?

APOLD1 p.Ser191Arg (c.571A>C) is classified Uncertain significance in APOLD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-16). AlphaMissense: likely pathogenic (0.8818); Ultra-rare (popmax 0.0123%, nfe).

How common is APOLD1 p.Ser191Arg (c.571A>C) in the general population?

APOLD1 p.Ser191Arg (c.571A>C) is ultra-rare (popmax 0.0123%, nfe) (gnomAD).

What do computational predictors say about APOLD1 p.Ser191Arg (c.571A>C)?

AlphaMissense predicts likely pathogenic (score 0.8818) — an in-silico prediction, not a clinical call.

APOLD1 p.Ser191Arg

c.571A>C · rs747928730 · VCV2485686

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8818 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8818	likely pathogenic · top 3% in APOLD1
REVEL	0.159	moderately benign-leaning
SaProt	LLR -6.54	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 6.9	GERP 2.7, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 1,957 bp · p 0.031 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S222R vs ClinVar S191R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0123% European (non-Finnish) · 145/1,180,036 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00997%

Overall 0.00911% 147/1,614,026 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0123%	8,138
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00133%	74,938

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.Ser191Arg
Coding: c.571A>C
MANE Select: NM_030817
dbSNP: rs747928730
Type: single nucleotide variant
Location: chr12:12787476 (GRCh38)
Gene constraint: LOEUF 1.959 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.17
Residue 191: 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.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-ser191arg (accessed [today's date]).

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