Is ACACB p.Ala650= (c.1950C>T) pathogenic?

ACACB p.Ala650= (c.1950C>T) is classified Likely benign in ACACB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-12-01). Ultra-rare (popmax 0.0658%, mid).

How common is ACACB p.Ala650= (c.1950C>T) in the general population?

ACACB p.Ala650= (c.1950C>T) is ultra-rare (popmax 0.0658%, mid) (gnomAD).

ACACB p.Ala650=

c.1950C>T · rs143351589 · VCV730800

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0658%, mid)

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 -11	GERP -4.2
Overall
CADD	0.43	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0658% Middle Eastern · 4/6,080 alleles

Filtering AF 0.0474% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0461%

Overall 0.0583% 939/1,611,160 alleles · ultra-rare exomes 829/1,459,110 · genomes 110/152,050 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.805%	124
Remaining individualsnot grpmax-eligible	0.0689%	1,450
Middle Easterngrpmax	0.0658%	1,520
European (non-Finnish)	0.0508%	1,967
Finnishnot grpmax-eligible	0.0375%	2,667
Admixed American	0.0351%	2,847
African / African-American	0.0107%	9,346
South Asian	0.0022%	45,381

Ashkenazi Jewish 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.Ala650=
Coding: c.1950C>T
MANE Select: NM_001093
dbSNP: rs143351589
Type: single nucleotide variant
Location: chr12:109185710 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.29 · 11 PDB
Residue 650: a β-strand; the biotin carboxylation domain

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.Arg1786Gln Likely benign ★★ same type
ACACB p.Asp1481Val Benign/Likely benign ★★ same type
ACACB p.Gln1257Glu Benign ★★ same type
ACACB p.Gly2305Ser Likely 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-ala650 (accessed [today's date]).

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