Is ABCC6 p.Leu673Pro (c.2018T>C) pathogenic?

ABCC6 p.Leu673Pro (c.2018T>C) is classified Pathogenic/Likely pathogenic in ABCC6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-10-03). AlphaMissense: likely pathogenic (0.6895); Very rare (popmax 0.00186%, nfe); Associated with ABCC6-related disorder.

What condition is associated with ABCC6 p.Leu673Pro (c.2018T>C)?

ABCC6 p.Leu673Pro (c.2018T>C) is associated with ABCC6-related disorder, autosomal recessive inherited pseudoxanthoma elasticum (ClinVar).

How common is ABCC6 p.Leu673Pro (c.2018T>C) in the general population?

ABCC6 p.Leu673Pro (c.2018T>C) is very rare (popmax 0.00186%, nfe) (gnomAD).

What do computational predictors say about ABCC6 p.Leu673Pro (c.2018T>C)?

AlphaMissense predicts likely pathogenic (score 0.6895) — an in-silico prediction, not a clinical call.

ABCC6 p.Leu673Pro

c.2018T>C · rs67470842 · VCV379930

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6895 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00186%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCC6-related disorder

Computational evidence

Protein change
AlphaMissense	0.6895	likely pathogenic ✓ concordant with ClinVar · top 10% in ABCC6
REVEL	0.966	strongly pathogenic-leaning
SaProt	LLR -13.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 59 kb · p 0.39 · regional, not allelic
Overall
CADD	29.5	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 0.00186% European (non-Finnish) · 22/1,180,004 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00149% 24/1,613,982 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00186%	53,637
Admixed American	0.00167%	60,010
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Leu673Pro
Coding: c.2018T>C
MANE Select: NM_001171
dbSNP: rs67470842
Type: single nucleotide variant
Location: chr16:16182856 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB
Residue 673: an α-helix; the abc transporter 1 domain; a UniProt-annotated variant site (in pxe; affects protein expression and trafficking; expression is reduced to less than 10%, when compared with the wt protein)

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

Disease context

ABCC6-related disorder

Also linked: autosomal recessive inherited pseudoxanthoma elasticum

Similar variants

ABCC6 p.Leu673= Likely benign ★★ same residue
ABCC6 c.1868-5T>G Pathogenic/Likely pathogenic ★★ same condition
ABCC6 c.2071-1G>A Likely pathogenic ★★ same condition
ABCC6 c.2591-1G>T Likely pathogenic ★★ same condition
ABCC6 c.2787+1G>T Pathogenic ★★ same condition
ABCC6 c.3506+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCC6 c.3507-1G>A Pathogenic ★★ same condition
ABCC6 c.37-1G>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-leu673pro (accessed [today's date]).

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