Is ACSF3 p.Val222= (c.666G>C) pathogenic?

ACSF3 p.Val222= (c.666G>C) is classified Uncertain significance in ACSF3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-03-13). Very rare (popmax 0.00135%, afr); Associated with combined malonic and methylmalonic acidemia.

What condition is associated with ACSF3 p.Val222= (c.666G>C)?

ACSF3 p.Val222= (c.666G>C) is associated with combined malonic and methylmalonic acidemia (ClinVar).

How common is ACSF3 p.Val222= (c.666G>C) in the general population?

ACSF3 p.Val222= (c.666G>C) is very rare (popmax 0.00135%, 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.Val222=

c.666G>C · VCV4066114

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Conditions

combined malonic and methylmalonic acidemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.63	donor loss · deltas
Pangolin	Δ0.51	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.6	GERP 1.8, phastCons 1
Overall
CADD	17.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00135% African / African-American · 1/74,314 alleles

Overall 0.00014% 2/1,427,480 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00135%	74,314
European (non-Finnish)	8.59e-05%	1,163,628

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.Val222=
Coding: c.666G>C
MANE Select: NM_001243279
Type: single nucleotide variant
Location: chr16:89101347 (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.Val222Ala 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-val222 (accessed [today's date]).

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