Is ACBD5 p.Arg425His (c.1274G>A) pathogenic?

ACBD5 p.Arg425His (c.1274G>A) is classified Uncertain significance in ACBD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-27). AlphaMissense: likely benign (0.175); Very rare (popmax 0.00329%, sas).

How common is ACBD5 p.Arg425His (c.1274G>A) in the general population?

ACBD5 p.Arg425His (c.1274G>A) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about ACBD5 p.Arg425His (c.1274G>A)?

AlphaMissense predicts likely benign (score 0.175) — an in-silico prediction, not a clinical call.

ACBD5 p.Arg425His

c.1274G>A · rs758175108 · VCV1905646

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.175 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.175	likely benign
REVEL	0.148	moderately benign-leaning
SaProt	LLR -7.50	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 3.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 43 kb · p 0.00076 · regional, not allelic
Overall
CADD	28.6	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 R434H vs ClinVar R425H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,082 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000743% 12/1,614,012 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,361
Admixed American	0.00167%	59,996
Remaining individualsnot grpmax-eligible	0.0016%	62,474
African / African-American	0.00133%	74,932
European (non-Finnish)	0.000508%	196,667

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: ACBD5
Protein: p.Arg425His
Coding: c.1274G>A
MANE Select: NM_145698
dbSNP: rs758175108
Type: single nucleotide variant
Location: chr10:27208376 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.49 · 1 PDB
Residue 425: the 'disordered' region

Full ACBD5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACBD5 p.Arg425Cys Uncertain significance ★ ⚠ same residue
ACBD5 p.Arg425Gly Uncertain significance ★ ⚠ same residue
ACBD5 p.Arg425Leu Uncertain significance ★ ⚠ same residue
ACBD5 p.Arg433Ter Pathogenic/Likely pathogenic ★★ same type
ACBD5 p.Ala182Thr Uncertain significance ★★ ⚠ same type
ACBD5 p.Arg384Trp Uncertain significance ★★ ⚠ same type
ACBD5 p.Arg415Trp Uncertain significance ★★ ⚠ same type
ACBD5 p.Asp429Asn 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/acbd5-p-arg425his (accessed [today's date]).

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