Is ACSF3 p.Pro508Leu (c.1523C>T) pathogenic?

ACSF3 p.Pro508Leu (c.1523C>T) is classified Uncertain significance in ACSF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-07). AlphaMissense: likely benign (0.1693); Ultra-rare (popmax 0.0334%, mid); Associated with combined malonic and methylmalonic acidemia.

What condition is associated with ACSF3 p.Pro508Leu (c.1523C>T)?

ACSF3 p.Pro508Leu (c.1523C>T) is associated with combined malonic and methylmalonic acidemia (ClinVar).

How common is ACSF3 p.Pro508Leu (c.1523C>T) in the general population?

ACSF3 p.Pro508Leu (c.1523C>T) is ultra-rare (popmax 0.0334%, mid) (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.Pro508Leu (c.1523C>T)?

AlphaMissense predicts likely benign (score 0.1693) — an in-silico prediction, not a clinical call.

ACSF3 p.Pro508Leu

c.1523C>T · VCV3708189

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1693 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

combined malonic and methylmalonic acidemia

Computational evidence

Protein change
AlphaMissense	0.1693	likely benign
REVEL	0.49	indeterminate
SaProt	LLR -12.56	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 0.32, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 54 kb · p 2.3e-09 · regional, not allelic
Overall
CADD	28.6	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 0.0334% Middle Eastern · 2/5,996 alleles

Filtering AF 0.00588% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.000812% 13/1,600,808 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0334%	2,998
Remaining individualsnot grpmax-eligible	0.00325%	30,799
East Asian	0.00228%	43,918
African / African-American	0.00135%	74,280
South Asian	0.0011%	90,914
European (non-Finnish)	0.000512%	195,264

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.Pro508Leu
Coding: c.1523C>T
MANE Select: NM_001243279
Type: single nucleotide variant
Location: chr16:89145959 (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.Pro508= Likely benign ★ 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
ACSF3 c.666+1G>T 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-pro508leu (accessed [today's date]).

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