Is ABCC1 p.Arg593Trp (c.1777C>T) pathogenic?

ABCC1 p.Arg593Trp (c.1777C>T) is classified Uncertain significance in ABCC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-02). AlphaMissense: likely pathogenic (0.9057); Ultra-rare (popmax 0.0165%, mid).

How common is ABCC1 p.Arg593Trp (c.1777C>T) in the general population?

ABCC1 p.Arg593Trp (c.1777C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ABCC1 p.Arg593Trp (c.1777C>T)?

AlphaMissense predicts likely pathogenic (score 0.9057) — an in-silico prediction, not a clinical call.

ABCC1 p.Arg593Trp

c.1777C>T · VCV3294819

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9057 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9057	likely pathogenic
REVEL	0.438	indeterminate
SaProt	LLR -15.06	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -0.89, phastCons 0.98
Regional constraint	o/e 0.88	unconstrained · MANE · 97 kb · p 2.5e-06 · regional, not allelic
Overall
CADD	34.0	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000616% 9/1,461,888 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0032%	31,250
European (non-Finnish)	0.000508%	196,672

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: ABCC1
Protein: p.Arg593Trp
Coding: c.1777C>T
MANE Select: NM_004996
Type: single nucleotide variant
Location: chr16:16068255 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.01 · 5 PDB
Residue 593: the abc transmembrane type-1 1 domain

Full ABCC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCC1 p.Thr1464Met Uncertain significance ★★ ⚠ same type
ABCC1 c.1381-5C>G Benign ★★ same type
ABCC1 p.Ala1260= Benign ★★ same type
ABCC1 p.Ala1406= Benign ★★ same type
ABCC1 p.Arg433Ser Benign ★★ same type
ABCC1 p.Asp637= Likely benign ★★ same type
ABCC1 p.Gly762= Benign/Likely benign ★★ same type
ABCC1 p.Gly885= 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/abcc1-p-arg593trp (accessed [today's date]).

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