Is ACSF3 p.Asp41Val (c.122A>T) pathogenic?

ACSF3 p.Asp41Val (c.122A>T) is classified Uncertain significance in ACSF3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-25). AlphaMissense: likely benign (0.1333); Ultra-rare (popmax 0.0386%, afr); Associated with combined malonic and methylmalonic acidemia.

What condition is associated with ACSF3 p.Asp41Val (c.122A>T)?

ACSF3 p.Asp41Val (c.122A>T) is associated with combined malonic and methylmalonic acidemia (ClinVar).

How common is ACSF3 p.Asp41Val (c.122A>T) in the general population?

ACSF3 p.Asp41Val (c.122A>T) is ultra-rare (popmax 0.0386%, 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.

What do computational predictors say about ACSF3 p.Asp41Val (c.122A>T)?

AlphaMissense predicts likely benign (score 0.1333) — an in-silico prediction, not a clinical call.

ACSF3 p.Asp41Val

c.122A>T · rs545886514 · VCV565935

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1333 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0386%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined malonic and methylmalonic acidemia

Computational evidence

Protein change
AlphaMissense	0.1333	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -6.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -0.38, phastCons 0.88
Regional constraint	o/e 1.22	unconstrained · MANE · 54 kb · p 2.3e-09 · regional, not allelic
Overall
CADD	16.05	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0386% African / African-American · 29/75,054 alleles

Filtering AF 0.0276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0238%

Overall 0.00186% 30/1,612,664 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0386%	2,588
European (non-Finnish)	8.47e-05%	1,180,004

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.Asp41Val
Coding: c.122A>T
MANE Select: NM_001243279
dbSNP: rs545886514
Type: single nucleotide variant
Location: chr16:89100803 (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.Asp41= Likely benign ★ same residue
ACSF3 p.Asp41Tyr Uncertain significance ⚠ same residue
ACSF3 p.Asp41Glu 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

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-asp41val (accessed [today's date]).

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