Is ABCB1 p.Arg1138Trp (c.3412C>T) pathogenic?

ABCB1 p.Arg1138Trp (c.3412C>T) is classified Uncertain significance in ABCB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-08-01). AlphaMissense: ambiguous (0.3472); Ultra-rare (popmax 0.0164%, mid); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with ABCB1 p.Arg1138Trp (c.3412C>T)?

ABCB1 p.Arg1138Trp (c.3412C>T) is associated with hereditary breast ovarian cancer syndrome (ClinVar).

How common is ABCB1 p.Arg1138Trp (c.3412C>T) in the general population?

ABCB1 p.Arg1138Trp (c.3412C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

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

What do computational predictors say about ABCB1 p.Arg1138Trp (c.3412C>T)?

AlphaMissense predicts ambiguous (score 0.3472) — an in-silico prediction, not a clinical call.

ABCB1 p.Arg1138Trp

c.3412C>T · rs773597757 · VCV981871

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3472 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.3472	ambiguous
REVEL	0.678	pathogenic-leaning
SaProt	LLR -17.15	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 96 kb · p 6.7e-09 · regional, not allelic
Overall
CADD	22.7	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00143% 23/1,613,948 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0064%	15,622
East Asian	0.00223%	44,896
African / African-American	0.00134%	74,886
European (non-Finnish)	0.00127%	78,666
South Asian	0.0011%	91,080

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: ABCB1
Protein: p.Arg1138Trp
Coding: c.3412C>T
MANE Select: NM_001348946
dbSNP: rs773597757
Type: single nucleotide variant
Location: chr7:87509352 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.72 · 24 PDB
Residue 1138: the abc transporter 2 domain; a UniProt-annotated variant site (in enpat; likely pathogenic)

Full ABCB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary breast ovarian cancer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

ABCB1 c.287-25G>T Benign ★★ same type
ABCB1 p.Ala1132= Benign/Likely benign ★★ same type
ABCB1 p.Gln1107Pro Benign/Likely benign ★★ same type
ABCB1 p.Glu243= Benign/Likely benign ★★ same type
ABCB1 p.Glu618= Likely benign ★★ same type
ABCB1 p.Gly412= Benign ★★ same type
ABCB1 p.Ile1145= Benign ★★ same type
ABCB1 p.Ile261Val Benign ★★ 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/abcb1-p-arg1138trp (accessed [today's date]).

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