Is ACSF3 p.Arg434Pro (c.1301G>C) pathogenic?

ACSF3 p.Arg434Pro (c.1301G>C) is classified Uncertain significance in ACSF3 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-09-26). AlphaMissense: likely pathogenic (0.7251); Ultra-rare (popmax 0.0775%, nfe); Associated with ACSF3-related disorder.

What condition is associated with ACSF3 p.Arg434Pro (c.1301G>C)?

ACSF3 p.Arg434Pro (c.1301G>C) is associated with ACSF3-related disorder, combined malonic and methylmalonic acidemia (ClinVar).

How common is ACSF3 p.Arg434Pro (c.1301G>C) in the general population?

ACSF3 p.Arg434Pro (c.1301G>C) is ultra-rare (popmax 0.0775%, nfe) (gnomAD).

What do computational predictors say about ACSF3 p.Arg434Pro (c.1301G>C)?

AlphaMissense predicts likely pathogenic (score 0.7251) — an in-silico prediction, not a clinical call.

ACSF3 p.Arg434Pro

c.1301G>C · rs137995833 · VCV419949

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.7251 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0775%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ACSF3-related disorder

Computational evidence

Protein change
AlphaMissense	0.7251	likely pathogenic
REVEL	0.284	benign-leaning
SaProt	LLR -14.20	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP -1.1, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 54 kb · p 2.3e-09 · regional, not allelic
Overall
CADD	20.9	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 0.0775% European (non-Finnish) · 914/1,180,024 alleles

Filtering AF 0.0733% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0716%

Overall 0.0619% 999/1,614,124 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0775%	1,291
Finnishnot grpmax-eligible	0.061%	1,641
Remaining individualsnot grpmax-eligible	0.048%	2,084
African / African-American	0.016%	6,253
Admixed American	0.005%	20,011
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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.Arg434Pro
Coding: c.1301G>C
MANE Select: NM_001243279
dbSNP: rs137995833
Type: single nucleotide variant
Location: chr16:89133197 (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

ACSF3-related disorder

Also linked: combined malonic and methylmalonic acidemia

Similar variants

ACSF3 p.Arg434Ter Pathogenic/Likely pathogenic ★★ same residue
ACSF3 p.Arg434fs Pathogenic/Likely pathogenic ★★ same residue
ACSF3 p.Arg434Gln 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-arg434pro (accessed [today's date]).

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