Is ABCB6 p.Arg192Trp (c.574C>T) pathogenic?

ABCB6 p.Arg192Trp (c.574C>T) is classified Benign/Likely benign in ABCB6 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-10-02). AlphaMissense: likely benign (0.3094); Rare (popmax 0.226%, nfe); Associated with hereditary coproporphyria.

What condition is associated with ABCB6 p.Arg192Trp (c.574C>T)?

ABCB6 p.Arg192Trp (c.574C>T) is associated with hereditary coproporphyria, acute intermittent porphyria, variegate porphyria (ClinVar).

How common is ABCB6 p.Arg192Trp (c.574C>T) in the general population?

ABCB6 p.Arg192Trp (c.574C>T) is rare (popmax 0.226%, nfe) (gnomAD).

How is Hereditary coproporphyria inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCB6 p.Arg192Trp (c.574C>T)?

AlphaMissense predicts likely benign (score 0.3094) — an in-silico prediction, not a clinical call.

ABCB6 p.Arg192Trp

c.574C>T · rs149202834 · VCV217872

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.3094 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.226%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary coproporphyria

Computational evidence

Protein change
AlphaMissense	0.3094	likely benign
REVEL	0.737	pathogenic-leaning
SaProt	LLR -12.47	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.2	GERP -1.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,732 bp · p 0.15 · regional, not allelic
Overall
CADD	24.7	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 0.226% European (non-Finnish) · 2,672/1,179,798 alleles

Filtering AF 0.219% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.216%

Overall 0.183% 2,956/1,613,266 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.226%	442
Finnishnot grpmax-eligible	0.171%	586
Remaining individualsnot grpmax-eligible	0.162%	619
Middle Eastern	0.132%	757
Admixed American	0.0368%	2,717
South Asian	0.0264%	3,793
African / African-American	0.024%	4,158
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,791

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.Arg192Trp
Coding: c.574C>T
MANE Select: NM_005689
dbSNP: rs149202834
Type: single nucleotide variant
Location: chr2:219217783 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.17 · 16 PDB
Residue 192: the 'required for atpase activity' region; the 'required for the lysosomal targeting' region; a UniProt-annotated variant site (decrease expression; does not affect substrate binding; does not affect atp-binding; loss of plasma membrane expression)

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

Disease context

hereditary coproporphyria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acute intermittent porphyria variegate porphyria protoporphyria, erythropoietic, 1

For Hereditary coproporphyria (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

ABCB6 p.Arg192Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCB6 p.Ala492Thr Benign/Likely benign ★★ ⚠ same condition
ABCB6 p.Arg247Cys Benign/Likely benign ★★ ⚠ same condition
ABCB6 p.Arg276Trp Benign/Likely benign ★★ same condition
ABCB6 p.Arg343Gln Benign/Likely benign ★★ ⚠ same condition
ABCB6 p.Thr521Ser Benign/Likely benign ★★ same condition
ABCB6 p.Gly588Ser Conflicting classifications of pathogenicity ★ ⚠ same condition
ABCB6 p.Gly729Ser 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-arg192trp (accessed [today's date]).

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