Is ACSF3 p.Arg286Gln (c.857G>A) pathogenic?

ACSF3 p.Arg286Gln (c.857G>A) is classified Uncertain significance in ACSF3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-10-19). AlphaMissense: likely benign (0.0762); Very rare (popmax 0.00574%, sas); Associated with methylmalonic acidemia.

What condition is associated with ACSF3 p.Arg286Gln (c.857G>A)?

ACSF3 p.Arg286Gln (c.857G>A) is associated with methylmalonic acidemia (ClinVar).

How common is ACSF3 p.Arg286Gln (c.857G>A) in the general population?

ACSF3 p.Arg286Gln (c.857G>A) is very rare (popmax 0.00574%, sas) (gnomAD).

What do computational predictors say about ACSF3 p.Arg286Gln (c.857G>A)?

AlphaMissense predicts likely benign (score 0.0762) — an in-silico prediction, not a clinical call.

ACSF3 p.Arg286Gln

c.857G>A · rs371654377 · VCV991079

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0762 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00574%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

methylmalonic acidemia

Computational evidence

Protein change
AlphaMissense	0.0762	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -4.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2	GERP -2.1, phastCons 0.082
Regional constraint	o/e 1.22	unconstrained · MANE · 54 kb · p 2.3e-09 · regional, not allelic
Overall
CADD	12.94	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 0.00574% South Asian · 3/52,228 alleles

Filtering AF 0.00152% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000822%

Overall 0.00118% 13/1,102,352 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00574%	17,409
Admixed American	0.00344%	29,054
African / African-American	0.00332%	30,148
European (non-Finnish)	0.000897%	111,456

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.Arg286Gln
Coding: c.857G>A
MANE Select: NM_001243279
dbSNP: rs371654377
Type: single nucleotide variant
Location: chr16:89112126 (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

methylmalonic acidemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACSF3 p.Arg286Trp Uncertain significance ★★ ⚠ same residue
ACSF3 p.Arg286= Likely benign ★ same residue
ACSF3 c.1613+3A>C Uncertain significance ★★ same condition
ACSF3 p.Ala44Thr Uncertain significance ★★ ⚠ same condition
ACSF3 p.Ala568Val Uncertain significance ★★ ⚠ same condition
ACSF3 p.Arg318His Uncertain significance ★★ ⚠ same condition
ACSF3 p.Arg39His Uncertain significance ★★ ⚠ same condition
ACSF3 p.Arg49Cys Uncertain significance ★★ ⚠ 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-arg286gln (accessed [today's date]).

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