Is ACSF3 p.Ser43= (c.129C>T) pathogenic?

ACSF3 p.Ser43= (c.129C>T) is classified Likely benign in ACSF3 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-16). Ultra-rare (popmax 0.0213%, afr); Associated with combined malonic and methylmalonic acidemia.

What condition is associated with ACSF3 p.Ser43= (c.129C>T)?

ACSF3 p.Ser43= (c.129C>T) is associated with combined malonic and methylmalonic acidemia (ClinVar).

How common is ACSF3 p.Ser43= (c.129C>T) in the general population?

ACSF3 p.Ser43= (c.129C>T) is ultra-rare (popmax 0.0213%, afr) (gnomAD).

How is Combined malonic and methylmalonic acidemia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ACSF3 p.Ser43=

c.129C>T · rs147915828 · VCV759856

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0213%, afr)

Conditions

combined malonic and methylmalonic acidemia

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 -8.6	GERP -3.3
Overall
CADD	0.975	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0213% African / African-American · 16/74,954 alleles

Filtering AF 0.0173% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0165%

Overall 0.0169% 272/1,612,690 alleles · ultra-rare exomes 246/1,460,452 · genomes 26/152,238 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0384%	2,603
African / African-Americangrpmax	0.0213%	4,685
European (non-Finnish)	0.0194%	5,153
South Asian	0.0022%	45,542
Admixed American	0.00167%	60,008

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: ACSF3
Protein: p.Ser43=
Coding: c.129C>T
MANE Select: NM_001243279
dbSNP: rs147915828
Type: single nucleotide variant
Location: chr16:89100810 (GRCh38)
Gene constraint: LOEUF 1.715 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.58

Full ACSF3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

combined malonic and methylmalonic acidemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined malonic and methylmalonic acidemia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (United States)

Similar variants

ACSF3 p.Ser43Arg Uncertain significance ⚠ same residue
ACSF3 c.1366+1G>A Likely pathogenic ★★ same condition
ACSF3 c.1501+1G>A Likely pathogenic ★★ same condition
ACSF3 c.1501+1G>T Likely pathogenic ★★ same condition
ACSF3 c.1502-2A>G Pathogenic/Likely pathogenic ★★ same condition
ACSF3 c.1613+1G>A Pathogenic/Likely pathogenic ★★ same condition
ACSF3 c.666+1G>A Pathogenic/Likely pathogenic ★★ same condition
ACSF3 c.666+1G>T Likely pathogenic ★★ 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/acsf3-p-ser43 (accessed [today's date]).

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