Is ABCC6 p.Arg1414Ser (c.4240C>A) pathogenic?

ABCC6 p.Arg1414Ser (c.4240C>A) is classified Likely pathogenic in ABCC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-04). AlphaMissense: likely pathogenic (0.6906); Ultra-rare (popmax 0.0483%, sas).

How common is ABCC6 p.Arg1414Ser (c.4240C>A) in the general population?

ABCC6 p.Arg1414Ser (c.4240C>A) is ultra-rare (popmax 0.0483%, sas) (gnomAD).

What do computational predictors say about ABCC6 p.Arg1414Ser (c.4240C>A)?

AlphaMissense predicts likely pathogenic (score 0.6906) — an in-silico prediction, not a clinical call.

ABCC6 p.Arg1414Ser

c.4240C>A · VCV3616170

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6906 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0483%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6906	likely pathogenic ✓ concordant with ClinVar · top 10% in ABCC6
REVEL	0.823	moderately pathogenic-leaning
SaProt	LLR -14.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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	25.8	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 0.0483% South Asian · 44/91,048 alleles

Filtering AF 0.0369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.033%

Overall 0.00322% 52/1,613,876 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0483%	2,069
Remaining individualsnot grpmax-eligible	0.0048%	20,835
European (non-Finnish)	0.000424%	235,990

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.Arg1414Ser
Coding: c.4240C>A
MANE Select: NM_001171
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.Arg1414Cys Conflicting classifications of pathogenicity ★ ⚠ 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-arg1414ser (accessed [today's date]).

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