Is ACSF3 p.Arg558Pro (c.1673G>C) pathogenic?

ACSF3 p.Arg558Pro (c.1673G>C) is classified Conflicting classifications of pathogenicity in ACSF3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-05-30). AlphaMissense: likely pathogenic (0.9103); Ultra-rare (popmax 0.0267%, afr); Associated with combined malonic and methylmalonic acidemia.

What condition is associated with ACSF3 p.Arg558Pro (c.1673G>C)?

ACSF3 p.Arg558Pro (c.1673G>C) is associated with combined malonic and methylmalonic acidemia, methylmalonic acidemia (ClinVar).

How common is ACSF3 p.Arg558Pro (c.1673G>C) in the general population?

ACSF3 p.Arg558Pro (c.1673G>C) is ultra-rare (popmax 0.0267%, 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.Arg558Pro (c.1673G>C)?

AlphaMissense predicts likely pathogenic (score 0.9103) — an in-silico prediction, not a clinical call.

ACSF3 p.Arg558Pro

c.1673G>C · rs140328142 · VCV992106

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9103 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

combined malonic and methylmalonic acidemia

Computational evidence

Protein change
AlphaMissense	0.9103	likely pathogenic · top 7% in ACSF3
REVEL	0.602	indeterminate
SaProt	LLR -11.78	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP 0.02, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 54 kb · p 2.3e-09 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0267% African / African-American · 20/74,988 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00155% 25/1,613,310 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0267%	3,749
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.000339%	294,932

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.Arg558Pro
Coding: c.1673G>C
MANE Select: NM_001243279
dbSNP: rs140328142
Type: single nucleotide variant
Location: chr16:89154149 (GRCh38)
Gene constraint: LOEUF 1.715 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.58
Residue 558: a UniProt-annotated variant site (in cmamma)

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

Also linked: methylmalonic acidemia

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.Arg558Trp Pathogenic/Likely pathogenic ★★ ⚠ same residue
ACSF3 p.Arg558Gln Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg558pro (accessed [today's date]).

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