Is ACBD6 p.Gln221Pro (c.662A>C) pathogenic?

ACBD6 p.Gln221Pro (c.662A>C) is classified Uncertain significance in ACBD6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-11). AlphaMissense: ambiguous (0.3703); Very rare (popmax 0.00153%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ACBD6 p.Gln221Pro (c.662A>C)?

ACBD6 p.Gln221Pro (c.662A>C) is associated with Inborn genetic diseases (ClinVar).

How common is ACBD6 p.Gln221Pro (c.662A>C) in the general population?

ACBD6 p.Gln221Pro (c.662A>C) is very rare (popmax 0.00153%, nfe) (gnomAD).

What do computational predictors say about ACBD6 p.Gln221Pro (c.662A>C)?

AlphaMissense predicts ambiguous (score 0.3703) — an in-silico prediction, not a clinical call.

ACBD6 p.Gln221Pro

c.662A>C · rs1280629166 · VCV3136057

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3703 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3703	ambiguous
REVEL	0.51	indeterminate
SaProt	LLR -9.61	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 214 kb · p 0.89 · regional, not allelic
Overall
CADD	26.5	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 0.00153% European (non-Finnish) · 18/1,178,262 alleles

Filtering AF 0.000955% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000788%

Overall 0.00118% 19/1,612,146 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,434
European (non-Finnish)grpmax	0.00153%	65,459

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Gln221Pro
Coding: c.662A>C
MANE Select: NM_032360
dbSNP: rs1280629166
Type: single nucleotide variant
Location: chr1:180397517 (GRCh38)
Gene constraint: LOEUF 1.037 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.80 · 1 PDB
Residue 221: a UniProt-annotated variant site (in nedpm; pathogenic); a UniProt-annotated variant site (in nedpm; likely pathogenic)

Full ACBD6 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

Similar variants

LHX4 p.Arg221Trp Uncertain significance ★ ⚠ same residue
LHX4 p.Ala354Val Uncertain significance ★★ ⚠ same condition
LHX4 p.Arg161Gln Uncertain significance ★★ ⚠ same condition
LHX4 p.Gly283Arg Uncertain significance ★★ ⚠ same condition
LHX4 p.His387Gln Uncertain significance ★★ ⚠ same condition
LHX4 p.Leu338Trp Uncertain significance ★★ ⚠ same condition
LHX4 p.Met286Thr Uncertain significance ★★ ⚠ same condition
LHX4 p.Ser230Asn 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/acbd6-p-gln221pro (accessed [today's date]).

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