Is ABCC6 p.Arg1153His (c.3458G>A) pathogenic?

ABCC6 p.Arg1153His (c.3458G>A) is classified Conflicting classifications of pathogenicity in ABCC6 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-06-14). AlphaMissense: likely benign (0.0722); Ultra-rare (popmax 0.016%, afr); Associated with Inborn genetic diseases.

What condition is associated with ABCC6 p.Arg1153His (c.3458G>A)?

ABCC6 p.Arg1153His (c.3458G>A) is associated with Inborn genetic diseases, pseudoxanthoma elasticum, forme fruste, autosomal recessive inherited pseudoxanthoma elasticum (ClinVar).

How common is ABCC6 p.Arg1153His (c.3458G>A) in the general population?

ABCC6 p.Arg1153His (c.3458G>A) is ultra-rare (popmax 0.016%, afr) (gnomAD).

What do computational predictors say about ABCC6 p.Arg1153His (c.3458G>A)?

AlphaMissense predicts likely benign (score 0.0722) — an in-silico prediction, not a clinical call.

ABCC6 p.Arg1153His

c.3458G>A · rs553479685 · VCV1394987

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0722 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0722	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -9.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.20	donor loss, 48 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.27	GERP -3.4
Regional constraint	o/e 0.98	unconstrained · MANE · 59 kb · p 0.39 · regional, not allelic
Overall
CADD	9.341	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 0.016% African / African-American · 12/75,060 alleles

Filtering AF 0.0092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00508% 82/1,614,052 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,255
South Asian	0.0154%	6,505
Admixed American	0.00833%	12,003
European (non-Finnish)	0.00398%	25,107
Remaining individualsnot grpmax-eligible	0.0032%	31,253
East Asian	0.00223%	44,888
Finnishnot grpmax-eligible	0.00157%	63,878

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.Arg1153His
Coding: c.3458G>A
MANE Select: NM_001171
dbSNP: rs553479685
Type: single nucleotide variant
Location: chr16:16163041 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB
Residue 1153: 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

Also linked: pseudoxanthoma elasticum, forme fruste autosomal recessive inherited pseudoxanthoma elasticum arterial calcification, generalized, of infancy, 2

Similar variants

ABCC6 p.Arg1153Cys Uncertain significance ★★ ⚠ same residue
ABCC6 p.Arg1153= Benign/Likely benign ★★ same residue
ABCC6 c.1868-5T>G Pathogenic/Likely pathogenic ★★ same condition
ABCC6 c.2591-1G>T Likely pathogenic ★★ same condition
ABCC6 c.2787+1G>T Pathogenic ★★ same condition
ABCC6 c.3507-1G>A Pathogenic ★★ same condition
ABCC6 c.37-1G>A Pathogenic ★★ same condition
ABCC6 c.3736-1G>A Pathogenic ★★ 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-arg1153his (accessed [today's date]).

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