Is ACSF3 p.Phe573fs (c.1718del) pathogenic?

ACSF3 p.Phe573fs (c.1718del) is classified Likely pathogenic in ACSF3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-18). Very rare (popmax 0.00254%, nfe); Associated with combined malonic and methylmalonic acidemia.

What condition is associated with ACSF3 p.Phe573fs (c.1718del)?

ACSF3 p.Phe573fs (c.1718del) is associated with combined malonic and methylmalonic acidemia (ClinVar).

How common is ACSF3 p.Phe573fs (c.1718del) in the general population?

ACSF3 p.Phe573fs (c.1718del) is very rare (popmax 0.00254%, nfe) (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.Phe573fs

c.1718del · rs796051924 · VCV203610

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00254%, nfe)

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	escapes	premature termination codon in the last exon (11 of 11) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.7	GERP -2.4, phastCons 0.075
Overall
CADD	20.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00254% European (non-Finnish) · 30/1,179,870 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00198% 32/1,613,456 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00254%	39,329
Admixed American	0.00167%	59,946
Remaining individualsnot grpmax-eligible	0.0016%	62,470

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.Phe573fs
Coding: c.1718del
MANE Select: NM_001243279
dbSNP: rs796051924
Type: Deletion
Location: chr16:89154193 (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.Phe573= Likely benign ★ same residue
ACSF3 p.Ala173fs Likely pathogenic ★★ same condition
ACSF3 p.Ala371fs Pathogenic/Likely pathogenic ★★ same condition
ACSF3 p.Ala52fs Pathogenic/Likely pathogenic ★★ same condition
ACSF3 p.Ala537fs Pathogenic/Likely pathogenic ★★ same condition
ACSF3 p.Arg434fs Pathogenic/Likely pathogenic ★★ same condition
ACSF3 p.Cys83fs Pathogenic/Likely pathogenic ★★ same condition
ACSF3 p.Cys88fs Pathogenic/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-phe573fs (accessed [today's date]).

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