Is ACBD3 p.Arg199Pro (c.596G>C) pathogenic?

ACBD3 p.Arg199Pro (c.596G>C) is classified Uncertain significance in ACBD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-18). AlphaMissense: likely pathogenic (0.9242); Very rare (popmax 0.00269%, afr).

How common is ACBD3 p.Arg199Pro (c.596G>C) in the general population?

ACBD3 p.Arg199Pro (c.596G>C) is very rare (popmax 0.00269%, afr) (gnomAD).

What do computational predictors say about ACBD3 p.Arg199Pro (c.596G>C)?

AlphaMissense predicts likely pathogenic (score 0.9242) — an in-silico prediction, not a clinical call.

ACBD3 p.Arg199Pro

c.596G>C · VCV3997451

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9242 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00269%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9242	likely pathogenic
REVEL	0.17	moderately benign-leaning
SaProt	LLR -14.64	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.77, phastCons 0.99
Regional constraint	o/e 0.83	unconstrained · MANE · 18 kb · p 0.00022 · regional, not allelic
Overall
CADD	24.0	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 0.00269% African / African-American · 2/74,344 alleles

Filtering AF 0.000446% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000167%

Overall 0.000187% 3/1,604,144 alleles · very rare exomes 1/1,452,056 · genomes 2/152,088 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00269%	37,172
European (non-Finnish)	8.51e-05%	1,175,132

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: ACBD3
Protein: p.Arg199Pro
Coding: c.596G>C
MANE Select: NM_022735
Type: single nucleotide variant
Location: chr1:226161663 (GRCh38)
Gene constraint: LOEUF 0.634 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.50 · 12 PDB
Residue 199: the 'charged amino-acid region (car)' region; the 'disordered' region

Full ACBD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACBD3 p.Arg199His Uncertain significance ★ ⚠ same residue
ACBD3 p.Arg199Leu Uncertain significance ★ ⚠ same residue
ACBD3 p.Ala177Glu Uncertain significance ★ ⚠ same type
ACBD3 p.Ala177Val Uncertain significance ★ ⚠ same type
ACBD3 p.Ala371Val Uncertain significance ★ ⚠ same type
ACBD3 p.Ala3Thr Uncertain significance ★ ⚠ same type
ACBD3 p.Ala442Asp Uncertain significance ★ ⚠ same type
ACBD3 p.Ala63Val 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/acbd3-p-arg199pro (accessed [today's date]).

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