Is ACSF3 p.Ala537= (c.1611C>T) pathogenic?

ACSF3 p.Ala537= (c.1611C>T) is classified Likely benign in ACSF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-02). Very rare (popmax 0.000121%, nfe); Associated with combined malonic and methylmalonic acidemia.

What condition is associated with ACSF3 p.Ala537= (c.1611C>T)?

ACSF3 p.Ala537= (c.1611C>T) is associated with combined malonic and methylmalonic acidemia (ClinVar).

How common is ACSF3 p.Ala537= (c.1611C>T) in the general population?

ACSF3 p.Ala537= (c.1611C>T) is very rare (popmax 0.000121%, 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.Ala537=

c.1611C>T · rs1342315943 · VCV2692647

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000121%, nfe)

Conditions

combined malonic and methylmalonic acidemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.471	indeterminate
Splicing
SpliceAI	Δ0.20	donor loss · deltas
Constraint at this position
Conservation	phyloP 0.18	GERP -2.9, phastCons 0.58
Overall
CADD	9.204	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000121% European (non-Finnish) · 1/828,838 alleles

Overall 9.65e-05% 1/1,035,764 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.Ala537=
Coding: c.1611C>T
MANE Select: NM_001243279
dbSNP: rs1342315943
Type: single nucleotide variant
Location: chr16:89146047 (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.Ala537fs Pathogenic/Likely pathogenic ★★ 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-ala537 (accessed [today's date]).

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