Is ABCC6 p.Arg1038Trp (c.3112C>T) pathogenic?

ABCC6 p.Arg1038Trp (c.3112C>T) is classified Uncertain significance in ABCC6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-09). AlphaMissense: likely benign (0.1112); Ultra-rare (popmax 0.0143%, sas); Associated with Inborn genetic diseases.

What condition is associated with ABCC6 p.Arg1038Trp (c.3112C>T)?

ABCC6 p.Arg1038Trp (c.3112C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ABCC6 p.Arg1038Trp (c.3112C>T) in the general population?

ABCC6 p.Arg1038Trp (c.3112C>T) is ultra-rare (popmax 0.0143%, sas) (gnomAD).

What do computational predictors say about ABCC6 p.Arg1038Trp (c.3112C>T)?

AlphaMissense predicts likely benign (score 0.1112) — an in-silico prediction, not a clinical call.

ABCC6 p.Arg1038Trp

c.3112C>T · VCV4129875

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1112 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1112	likely benign
REVEL	0.316	indeterminate
SaProt	LLR -7.84	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -0.56, phastCons 0.6
Regional constraint	o/e 0.98	unconstrained · MANE · 59 kb · p 0.39 · regional, not allelic
Overall
CADD	18.46	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0143% South Asian · 13/91,084 alleles

Filtering AF 0.00844% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00661%

Overall 0.00167% 27/1,613,442 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0143%	7,006
Remaining individualsnot grpmax-eligible	0.0048%	20,827
African / African-American	0.004%	24,975
Finnishnot grpmax-eligible	0.00158%	63,406
European (non-Finnish)	0.000593%	168,578

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: ABCC6
Protein: p.Arg1038Trp
Coding: c.3112C>T
MANE Select: NM_001171
Type: single nucleotide variant
Location: chr16:16165817 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB
Residue 1038: the abc transmembrane type-1 2 domain

Full ABCC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABCC6 p.Arg1038Gln Uncertain significance ★★ ⚠ same residue
ABCC6 p.Arg1038= Likely benign ★ same residue
ABCC6 p.Ala1008Val Uncertain significance ★★ ⚠ same condition
ABCC6 p.Ala101Gly Uncertain significance ★★ ⚠ same condition
ABCC6 p.Ala1370Thr Uncertain significance ★★ ⚠ same condition
ABCC6 p.Ala1385Val Uncertain significance ★★ ⚠ same condition
ABCC6 p.Ala263Gly Uncertain significance ★★ ⚠ same condition
ABCC6 p.Ala353Thr Uncertain significance ★★ ⚠ 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/abcc6-p-arg1038trp (accessed [today's date]).

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