Is ACSF3 p.Ala173fs (c.516_522del) pathogenic?

ACSF3 p.Ala173fs (c.516522del) is classified Likely pathogenic in ACSF3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-05). Very rare (popmax 0.00515%, amr); Associated with combined malonic and methylmalonic acidemia.

What condition is associated with ACSF3 p.Ala173fs (c.516_522del)?

ACSF3 p.Ala173fs (c.516_522del) is associated with combined malonic and methylmalonic acidemia (ClinVar).

How common is ACSF3 p.Ala173fs (c.516_522del) in the general population?

ACSF3 p.Ala173fs (c.516_522del) is very rare (popmax 0.00515%, amr) (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.Ala173fs

c.516_522del · rs761494200 · VCV3240966

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00515%, amr)

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 -0.048	GERP 0.66

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00515% Admixed American · 3/58,296 alleles

Filtering AF 0.00137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000679%

Overall 0.000206% 3/1,455,866 alleles · very rare

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.Ala173fs
Coding: c.516_522del
MANE Select: NM_001243279
dbSNP: rs761494200
Type: Deletion
Location: chr16:89101196 (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.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
ACSF3 p.Glu424fs Pathogenic/Likely pathogenic ★★ same condition
ACSF3 p.Leu335fs 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-ala173fs (accessed [today's date]).

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