Is ABCB6 p.Arg276Pro (c.827G>C) pathogenic?

ABCB6 p.Arg276Pro (c.827G>C) is classified Uncertain significance in ABCB6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-08). AlphaMissense: likely pathogenic (0.991); Very rare (popmax 0.000172%, nfe).

How common is ABCB6 p.Arg276Pro (c.827G>C) in the general population?

ABCB6 p.Arg276Pro (c.827G>C) is very rare (popmax 0.000172%, nfe) (gnomAD).

What do computational predictors say about ABCB6 p.Arg276Pro (c.827G>C)?

AlphaMissense predicts likely pathogenic (score 0.991) — an in-silico prediction, not a clinical call.

ABCB6 p.Arg276Pro

c.827G>C · VCV3379422

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.991 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000172%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.991	likely pathogenic · top 2% in ABCB6
REVEL	0.913	moderately pathogenic-leaning
SaProt	LLR -17.40	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,732 bp · p 0.15 · regional, not allelic
Overall
CADD	29.9	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 0.000172% European (non-Finnish) · 2/1,165,302 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000126% 2/1,583,934 alleles · very rare exomes 2/1,431,688 · genomes 0/152,246 · joint denominator

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.Arg276Pro
Coding: c.827G>C
MANE Select: NM_005689
Type: single nucleotide variant
Location: chr2:219216693 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.17 · 16 PDB
Residue 276: the abc transmembrane type-1 domain; a UniProt-annotated variant site (may be a modifier of disease severity in porphyria patients; loss of expression); an α-helix

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

Similar variants

ABCB6 p.Arg276Trp Benign/Likely benign ★★ same residue
ABCB6 p.Arg276Gln Uncertain significance ★ ⚠ same residue
ABCB6 p.Ala164Thr Uncertain significance ★★ ⚠ same type
ABCB6 p.Ala57Thr Uncertain significance ★★ ⚠ same type
ABCB6 p.Ala66Thr Uncertain significance ★★ ⚠ same type
ABCB6 p.Ala681Thr Uncertain significance ★★ ⚠ same type
ABCB6 p.Arg135Ser Uncertain significance ★★ ⚠ same type
ABCB6 p.Arg439Cys 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/abcb6-p-arg276pro (accessed [today's date]).

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