Is ABCB6 p.Arg450Trp (c.1348C>T) pathogenic?

ABCB6 p.Arg450Trp (c.1348C>T) is classified Likely pathogenic in ABCB6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-08-26). AlphaMissense: ambiguous (0.4876); Ultra-rare (popmax 0.0165%, mid); Associated with microphthalmia, isolated, with coloboma 7.

What condition is associated with ABCB6 p.Arg450Trp (c.1348C>T)?

ABCB6 p.Arg450Trp (c.1348C>T) is associated with microphthalmia, isolated, with coloboma 7 (ClinVar).

How common is ABCB6 p.Arg450Trp (c.1348C>T) in the general population?

ABCB6 p.Arg450Trp (c.1348C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ABCB6 p.Arg450Trp (c.1348C>T)?

AlphaMissense predicts ambiguous (score 0.4876) — an in-silico prediction, not a clinical call.

ABCB6 p.Arg450Trp

c.1348C>T · VCV4086262

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4876 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

microphthalmia, isolated, with coloboma 7

Computational evidence

Protein change
AlphaMissense	0.4876	ambiguous
REVEL	0.636	indeterminate
SaProt	LLR -11.77	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP 1.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,732 bp · p 0.15 · regional, not allelic
Overall
CADD	28.1	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00185% 27/1,461,842 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.008%	12,501
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,802
Admixed American	0.00333%	30,011
European (non-Finnish)	0.00144%	69,412

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: ABCB6
Protein: p.Arg450Trp
Coding: c.1348C>T
MANE Select: NM_005689
Type: single nucleotide variant
Location: chr2:219214427 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.17 · 16 PDB
Residue 450: the abc transmembrane type-1 domain; an α-helix

Full ABCB6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microphthalmia, isolated, with coloboma 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABCB6 p.Arg450Gln Uncertain significance ★★ ⚠ same residue
ABCB6 p.Ala57Thr Uncertain significance ★★ ⚠ same condition
ABCB6 p.Arg739Cys Uncertain significance ★★ ⚠ same condition
ABCB6 p.Gly317Trp Uncertain significance ★★ ⚠ same condition
ABCB6 c.688-9C>T Benign/Likely benign ★★ same condition
ABCB6 c.1864-4A>G Uncertain significance ★ same condition
ABCB6 p.Arg192Gln Conflicting classifications of pathogenicity ★ ⚠ same condition
ABCB6 p.Arg375Trp Conflicting classifications of pathogenicity ★ 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/abcb6-p-arg450trp (accessed [today's date]).

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