Is ACBD6 p.Val75Phe (c.223G>T) pathogenic?

ACBD6 p.Val75Phe (c.223G>T) is classified Uncertain significance in ACBD6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-11). AlphaMissense: likely pathogenic (0.7513); Very rare (popmax 0.00502%, amr); Associated with neurodevelopmental disorder with progressive movement abnormalities.

What condition is associated with ACBD6 p.Val75Phe (c.223G>T)?

ACBD6 p.Val75Phe (c.223G>T) is associated with neurodevelopmental disorder with progressive movement abnormalities (ClinVar).

How common is ACBD6 p.Val75Phe (c.223G>T) in the general population?

ACBD6 p.Val75Phe (c.223G>T) is very rare (popmax 0.00502%, amr) (gnomAD).

What do computational predictors say about ACBD6 p.Val75Phe (c.223G>T)?

AlphaMissense predicts likely pathogenic (score 0.7513) — an in-silico prediction, not a clinical call.

ACBD6 p.Val75Phe

c.223G>T · VCV4072256

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7513 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00502%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neurodevelopmental disorder with progressive movement abnormalities

Computational evidence

Protein change
AlphaMissense	0.7513	likely pathogenic
REVEL	0.294	indeterminate
SaProt	LLR -11.82	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.79	acceptor loss · deltas
Pangolin	Δ0.68	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 214 kb · p 0.89 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00502% Admixed American · 3/59,802 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000669%

Overall 0.000206% 3/1,456,062 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: ACBD6
Protein: p.Val75Phe
Coding: c.223G>T
MANE Select: NM_032360
Type: single nucleotide variant
Location: chr1:180495525 (GRCh38)
Gene constraint: LOEUF 1.037 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.80 · 1 PDB
Residue 75: the acb domain; a UniProt-annotated variant site (in nedpm; pathogenic); an α-helix

Full ACBD6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with progressive movement abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACBD6 p.Glu63Ter Pathogenic ★ same condition
ACBD6 c.574-2A>G Uncertain significance ★ same condition
ACBD6 p.Leu121fs Pathogenic ★ same condition
ACBD6 p.Asn161_Ile162insTer Pathogenic same condition
ACBD6 p.Asp159fs Pathogenic same condition
ACBD6 p.Val28fs Pathogenic same condition
LHX4 c.*17C>T Uncertain significance ★★ same type
LHX4 p.Ala354Val Uncertain significance ★★ ⚠ same type

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/acbd6-p-val75phe (accessed [today's date]).

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