Is ABCC6 p.Pro49Ala (c.145C>G) pathogenic?

ABCC6 p.Pro49Ala (c.145C>G) is classified Uncertain significance in ABCC6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-22). AlphaMissense: likely benign (0.2956); Rare (popmax 0.127%, amr); Associated with Inborn genetic diseases.

What condition is associated with ABCC6 p.Pro49Ala (c.145C>G)?

ABCC6 p.Pro49Ala (c.145C>G) is associated with Inborn genetic diseases, pseudoxanthoma elasticum, forme fruste, autosomal recessive inherited pseudoxanthoma elasticum (ClinVar).

How common is ABCC6 p.Pro49Ala (c.145C>G) in the general population?

ABCC6 p.Pro49Ala (c.145C>G) is rare (popmax 0.127%, amr) (gnomAD).

What do computational predictors say about ABCC6 p.Pro49Ala (c.145C>G)?

AlphaMissense predicts likely benign (score 0.2956) — an in-silico prediction, not a clinical call.

ABCC6 p.Pro49Ala

c.145C>G · VCV3302890

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2956 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.127%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2956	likely benign
REVEL	0.423	indeterminate
SaProt	LLR -11.96	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP -0.71, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 158 bp · p 0.68 · regional, not allelic
Overall
CADD	24.3	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 0.127% Admixed American · 76/59,958 alleles

Filtering AF 0.104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0954%

Overall 0.0049% 79/1,613,716 alleles · rare exomes 70/1,461,576 · genomes 9/152,140 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.127%	789
African / African-American	0.00267%	37,446
Remaining individualsnot grpmax-eligible	0.0016%	62,460

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.Pro49Ala
Coding: c.145C>G
MANE Select: NM_001171
Type: single nucleotide variant
Location: chr16:16221723 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB

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 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
ABCC6 c.3883-6G>A Pathogenic/Likely pathogenic ★★ same condition
ABCC6 c.4209-2A>C Pathogenic/Likely 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-pro49ala (accessed [today's date]).

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