Is ACSF3 p.Arg558Trp (c.1672C>T) pathogenic?

ACSF3 p.Arg558Trp (c.1672C>T) is classified Pathogenic/Likely pathogenic in ACSF3 (ClinVar, Multiple submitters, 23 submitters; last evaluated 2026-03-01). AlphaMissense: ambiguous (0.4287); Rare (popmax 0.578%, nfe); Associated with ACSF3-related disorder.

What condition is associated with ACSF3 p.Arg558Trp (c.1672C>T)?

ACSF3 p.Arg558Trp (c.1672C>T) is associated with ACSF3-related disorder, combined malonic and methylmalonic acidemia (ClinVar).

How common is ACSF3 p.Arg558Trp (c.1672C>T) in the general population?

ACSF3 p.Arg558Trp (c.1672C>T) is rare (popmax 0.578%, nfe) (gnomAD).

What do computational predictors say about ACSF3 p.Arg558Trp (c.1672C>T)?

AlphaMissense predicts ambiguous (score 0.4287) — an in-silico prediction, not a clinical call.

ACSF3 p.Arg558Trp

c.1672C>T · rs141090143 · VCV31134

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 23 submitters

AlphaMissense

ambiguous

0.4287 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.578%, nfe)

Conditions

ACSF3-related disorder

Computational evidence

Protein change
AlphaMissense	0.4287	ambiguous
REVEL	0.503	indeterminate
SaProt	LLR -12.88	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -2.4, phastCons 0.47
Regional constraint	o/e 1.22	unconstrained · MANE · 54 kb · p 2.3e-09 · regional, not allelic
Overall
CADD	23.5	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 0.578% European (non-Finnish) · 6,822/1,179,774 alleles

Filtering AF 0.567% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.562%

Overall 0.452% 7,287/1,613,416 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.578%	173
Remaining individualsnot grpmax-eligible	0.405%	247
Finnishnot grpmax-eligible	0.119%	841
Admixed American	0.103%	966
African / African-American	0.0947%	1,056
Middle Eastern	0.0165%	6,060
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,590
South Asian	0.0011%	90,846

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.Arg558Trp
Coding: c.1672C>T
MANE Select: NM_001243279
dbSNP: rs141090143
Type: single nucleotide variant
Location: chr16:89154148 (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

ACSF3-related disorder

Also linked: combined malonic and methylmalonic acidemia

Similar variants

ACSF3 p.Arg558Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
ACSF3 p.Arg558Pro 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-arg558trp (accessed [today's date]).

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