Is ACSF3 p.Val339Ala (c.1016T>C) pathogenic?

ACSF3 p.Val339Ala (c.1016T>C) is classified Uncertain significance in ACSF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-20). AlphaMissense: likely benign (0.2473); Ultra-rare (popmax 0.02%, afr); Associated with combined malonic and methylmalonic acidemia.

What condition is associated with ACSF3 p.Val339Ala (c.1016T>C)?

ACSF3 p.Val339Ala (c.1016T>C) is associated with combined malonic and methylmalonic acidemia (ClinVar).

How common is ACSF3 p.Val339Ala (c.1016T>C) in the general population?

ACSF3 p.Val339Ala (c.1016T>C) is ultra-rare (popmax 0.02%, 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.Val339Ala (c.1016T>C)?

AlphaMissense predicts likely benign (score 0.2473) — an in-silico prediction, not a clinical call.

ACSF3 p.Val339Ala

c.1016T>C · rs768294145 · VCV2921122

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2473 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined malonic and methylmalonic acidemia

Computational evidence

Protein change
AlphaMissense	0.2473	likely benign
REVEL	0.263	benign-leaning
SaProt	LLR -12.61	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.41 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 54 kb · p 2.3e-09 · regional, not allelic
Overall
CADD	24.3	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 0.02% African / African-American · 15/74,912 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00989%

Overall 0.000991% 16/1,613,930 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.02%	4,994
European (non-Finnish)	8.47e-05%	1,180,036

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.Val339Ala
Coding: c.1016T>C
MANE Select: NM_001243279
dbSNP: rs768294145
Type: single nucleotide variant
Location: chr16:89114377 (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.Val339Leu Uncertain significance ★ ⚠ same residue
ACSF3 p.Val339Met 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
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-val339ala (accessed [today's date]).

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