Is ABCC6 p.Ala353Thr (c.1057G>A) pathogenic?

ABCC6 p.Ala353Thr (c.1057G>A) is classified Uncertain significance in ABCC6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-05). AlphaMissense: likely benign (0.1472); Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

What condition is associated with ABCC6 p.Ala353Thr (c.1057G>A)?

ABCC6 p.Ala353Thr (c.1057G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ABCC6 p.Ala353Thr (c.1057G>A) in the general population?

ABCC6 p.Ala353Thr (c.1057G>A) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about ABCC6 p.Ala353Thr (c.1057G>A)?

AlphaMissense predicts likely benign (score 0.1472) — an in-silico prediction, not a clinical call.

ABCC6 p.Ala353Thr

c.1057G>A · rs774051128 · VCV2338677

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1472 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1472	likely benign
REVEL	0.673	pathogenic-leaning
SaProt	LLR -9.31	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 1.1, phastCons 0.91
Regional constraint	o/e 0.98	unconstrained · MANE · 59 kb · p 0.39 · regional, not allelic
Overall
CADD	24.2	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 0.00534% African / African-American · 4/74,854 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00302%

Overall 0.00372% 60/1,613,730 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,713
Remaining individualsnot grpmax-eligible	0.0048%	20,823
European (non-Finnish)	0.00432%	23,135
Admixed American	0.00333%	29,990

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.Ala353Thr
Coding: c.1057G>A
MANE Select: NM_001171
dbSNP: rs774051128
Type: single nucleotide variant
Location: chr16:16202120 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB
Residue 353: the abc transmembrane type-1 1 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

Similar variants

ABCC6 p.Ala353Val Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCC6 p.Ala353= Benign/Likely benign ★★ same residue
ABCC6 p.Ala1008Val Uncertain significance ★★ ⚠ same condition
ABCC6 p.Ala101Gly Uncertain significance ★★ ⚠ same condition
ABCC6 p.Ala1370Thr Uncertain significance ★★ ⚠ same condition
ABCC6 p.Ala1385Val Uncertain significance ★★ ⚠ same condition
ABCC6 p.Ala263Gly Uncertain significance ★★ ⚠ same condition
ABCC6 p.Ala488Thr Uncertain significance ★★ ⚠ 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-ala353thr (accessed [today's date]).

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