Is ABCC6 p.Arg1414Cys (c.4240C>T) pathogenic?

ABCC6 p.Arg1414Cys (c.4240C>T) is classified Conflicting classifications of pathogenicity in ABCC6 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-29). AlphaMissense: likely benign (0.2376); Very rare (popmax 0.00446%, eas).

How common is ABCC6 p.Arg1414Cys (c.4240C>T) in the general population?

ABCC6 p.Arg1414Cys (c.4240C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about ABCC6 p.Arg1414Cys (c.4240C>T)?

AlphaMissense predicts likely benign (score 0.2376) — an in-silico prediction, not a clinical call.

ABCC6 p.Arg1414Cys

c.4240C>T · rs760611511 · VCV1430174

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2376 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2376	likely benign
REVEL	0.795	moderately pathogenic-leaning
SaProt	LLR -12.63	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.97 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.5	GERP -0.67, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 59 kb · p 0.39 · regional, not allelic
Overall
CADD	29.0	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 0.00446% East Asian · 2/44,874 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00192% 31/1,613,758 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,621
East Asiangrpmax	0.00446%	22,437
European (non-Finnish)	0.00203%	49,165
South Asian	0.0011%	91,052

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1414Cys
Coding: c.4240C>T
MANE Select: NM_001171
dbSNP: rs760611511
Type: single nucleotide variant
Location: chr16:16150741 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB
Residue 1414: an α-helix; the abc transporter 2 domain

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

Similar variants

ABCC6 p.Arg1414His Uncertain significance ★★ ⚠ same residue
ABCC6 p.Arg1414Ser Likely pathogenic ★ same residue
ABCC6 c.1868-5T>G Pathogenic/Likely pathogenic ★★ same type
ABCC6 c.2071-1G>A Likely pathogenic ★★ same type
ABCC6 c.2591-1G>T Likely pathogenic ★★ same type
ABCC6 c.2787+1G>T Pathogenic ★★ same type
ABCC6 c.3506+1G>A Pathogenic/Likely pathogenic ★★ same type
ABCC6 c.3507-1G>A Pathogenic ★★ 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/abcc6-p-arg1414cys (accessed [today's date]).

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