Is ACACB p.Phe1375= (c.4125C>T) pathogenic?

ACACB p.Phe1375= (c.4125C>T) is classified Likely benign in ACACB (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-09-18). Rare (popmax 0.2%, afr); Associated with ACACB-related disorder.

What condition is associated with ACACB p.Phe1375= (c.4125C>T)?

ACACB p.Phe1375= (c.4125C>T) is associated with ACACB-related disorder (ClinVar).

How common is ACACB p.Phe1375= (c.4125C>T) in the general population?

ACACB p.Phe1375= (c.4125C>T) is rare (popmax 0.2%, afr) (gnomAD).

ACACB p.Phe1375=

c.4125C>T · rs137881698 · VCV3048560

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.2%, afr)

Conditions

ACACB-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.7	GERP -3.9
Overall
CADD	8.254	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.2% African / African-American · 150/75,026 alleles

Filtering AF 0.174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.164%

Overall 0.0116% 188/1,614,100 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.2%	500
Middle Eastern	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.0144%	6,945
Admixed American	0.0117%	8,572
South Asian	0.00549%	18,216
European (non-Finnish)	0.00136%	73,751

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.Phe1375=
Coding: c.4125C>T
MANE Select: NM_001093
dbSNP: rs137881698
Type: single nucleotide variant
Location: chr12:109232792 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.29 · 11 PDB

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

Disease context

ACACB-related disorder

Similar variants

ACACB p.Arg939Ser Conflicting classifications of pathogenicity ★ ⚠ same condition
ACACB p.Phe578Leu Uncertain significance ★ ⚠ same condition
ACACB p.Ser1199= Conflicting classifications of pathogenicity ★ same condition
ACACB p.Glu1608Lys Uncertain significance ⚠ same condition
ACACB p.Met1253Thr Uncertain significance ⚠ same condition
ACACB p.Met2164Thr Uncertain significance ⚠ same condition
ACACB c.1117+3A>G Likely benign same condition
ACACB c.1819-7A>G Likely benign same condition

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-phe1375 (accessed [today's date]).

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