Is ACACB p.Arg615Trp (c.1843C>T) pathogenic?

ACACB p.Arg615Trp (c.1843C>T) is classified Uncertain significance in ACACB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-12). AlphaMissense: likely benign (0.2204); Very rare (popmax 0.00958%, nfe).

How common is ACACB p.Arg615Trp (c.1843C>T) in the general population?

ACACB p.Arg615Trp (c.1843C>T) is very rare (popmax 0.00958%, nfe) (gnomAD).

What do computational predictors say about ACACB p.Arg615Trp (c.1843C>T)?

AlphaMissense predicts likely benign (score 0.2204) — an in-silico prediction, not a clinical call.

ACACB p.Arg615Trp

c.1843C>T · VCV3805185

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2204 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00958%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2204	likely benign
REVEL	0.899	moderately pathogenic-leaning
SaProt	LLR -14.79	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.14	GERP -1.5, phastCons 0.89
Regional constraint	o/e 0.88	unconstrained · MANE · 111 kb · p 4.8e-09 · regional, not allelic
Overall
CADD	25.5	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 0.00958% European (non-Finnish) · 113/1,179,968 alleles

Filtering AF 0.00809% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0076%

Overall 0.00781% 126/1,613,702 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0096%	10,413
European (non-Finnish)grpmax	0.00958%	10,442
African / African-American	0.00401%	24,964
Admixed American	0.00334%	29,982
Finnishnot grpmax-eligible	0.00157%	63,878
South Asian	0.0011%	91,060

Remaining individuals 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: ACACB
Protein: p.Arg615Trp
Coding: c.1843C>T
MANE Select: NM_001093
Type: single nucleotide variant
Location: chr12:109185603 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.29 · 11 PDB
Residue 615: the biotin carboxylation domain; an α-helix

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

Similar variants

ACACB p.Val958Met Uncertain significance ★★ ⚠ same type
ACACB c.6942+9C>T Benign ★★ same type
ACACB c.6943-8G>A Benign ★★ same type
ACACB c.7113+7C>T Benign/Likely benign ★★ same type
ACACB p.Ala650= Likely benign ★★ same type
ACACB p.Arg1786Gln Likely benign ★★ ⚠ same type
ACACB p.Asp1481Val Benign/Likely benign ★★ ⚠ same type
ACACB p.Gln1257Glu Benign ★★ 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/acacb-p-arg615trp (accessed [today's date]).

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