Is ACSF3 p.Arg74fs (c.220dup) pathogenic?

ACSF3 p.Arg74fs (c.220dup) is classified Pathogenic in ACSF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-14). Absent from gnomAD; Associated with combined malonic and methylmalonic acidemia.

What condition is associated with ACSF3 p.Arg74fs (c.220dup)?

ACSF3 p.Arg74fs (c.220dup) is associated with combined malonic and methylmalonic acidemia (ClinVar).

How common is ACSF3 p.Arg74fs (c.220dup) in the general population?

ACSF3 p.Arg74fs (c.220dup) is absent from gnomAD (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.Arg74fs

c.220dup · rs2543520647 · VCV2703212

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

combined malonic and methylmalonic acidemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.73	GERP -3.6

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ACSF3
Protein: p.Arg74fs
Coding: c.220dup
MANE Select: NM_001243279
dbSNP: rs2543520647
Type: Duplication
Location: chr16:89100898 (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.Arg74Cys Uncertain significance ★ ⚠ same residue
ACSF3 p.Arg74His Uncertain significance ★ ⚠ same residue
ACSF3 p.Ala253fs Pathogenic/Likely pathogenic ★★ same condition
ACSF3 p.His526fs Likely pathogenic ★★ same condition
ACSF3 p.Leu522fs Likely pathogenic ★★ same condition
ACSF3 p.Lys444Ter Pathogenic/Likely pathogenic ★★ same condition
ACSF3 p.Val460fs Pathogenic/Likely pathogenic ★★ same condition
ACSF3 p.Val484fs 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-arg74fs (accessed [today's date]).

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