Is ACSF3 p.Ser144Phe (c.431C>T) pathogenic?

ACSF3 p.Ser144Phe (c.431C>T) is classified Uncertain significance in ACSF3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-26). AlphaMissense: likely benign (0.205); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

What condition is associated with ACSF3 p.Ser144Phe (c.431C>T)?

ACSF3 p.Ser144Phe (c.431C>T) is associated with Inborn genetic diseases, combined malonic and methylmalonic acidemia (ClinVar).

How common is ACSF3 p.Ser144Phe (c.431C>T) in the general population?

ACSF3 p.Ser144Phe (c.431C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about ACSF3 p.Ser144Phe (c.431C>T)?

AlphaMissense predicts likely benign (score 0.205) — an in-silico prediction, not a clinical call.

ACSF3 p.Ser144Phe

c.431C>T · rs774006659 · VCV651756

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.205 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.205	likely benign
REVEL	0.306	indeterminate
SaProt	LLR -12.29	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 3.1	GERP 1.8, phastCons 0.98
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 0.004% African / African-American · 3/74,936 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,613,998 alleles · very rare

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.Ser144Phe
Coding: c.431C>T
MANE Select: NM_001243279
dbSNP: rs774006659
Type: single nucleotide variant
Location: chr16:89101112 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: combined malonic and methylmalonic acidemia

Similar variants

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
ACSF3 c.667-2A>G 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-ser144phe (accessed [today's date]).

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