Is ABCC8 p.Ala726Thr (c.2176G>A) pathogenic?

ABCC8 p.Ala726Thr (c.2176G>A) is classified Conflicting classifications of pathogenicity in ABCC8 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0741); Rare (popmax 0.103%, nfe); Associated with pulmonary arterial hypertension.

What condition is associated with ABCC8 p.Ala726Thr (c.2176G>A)?

ABCC8 p.Ala726Thr (c.2176G>A) is associated with pulmonary arterial hypertension, type 2 diabetes mellitus, hypoglycemia, leucine-induced (ClinVar).

How common is ABCC8 p.Ala726Thr (c.2176G>A) in the general population?

ABCC8 p.Ala726Thr (c.2176G>A) is rare (popmax 0.103%, nfe) (gnomAD).

What do computational predictors say about ABCC8 p.Ala726Thr (c.2176G>A)?

AlphaMissense predicts likely benign (score 0.0741) — an in-silico prediction, not a clinical call.

ABCC8 p.Ala726Thr

Q: How is Idiopathic/heritable pulmonary arterial hypertension inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.2176G>A · rs138687850 · VCV434050

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0741 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.103%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pulmonary arterial hypertension

Computational evidence

Protein change
AlphaMissense	0.0741	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -6.03	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -0.75, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	14.63	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 0.103% European (non-Finnish) · 1,215/1,179,910 alleles

Filtering AF 0.0981% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0962%

Overall 0.081% 1,307/1,613,880 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.103%	971
Remaining individualsnot grpmax-eligible	0.0544%	1,838
Admixed American	0.0433%	2,307
African / African-American	0.0293%	3,409
Middle Eastern	0.0165%	6,060
Finnishnot grpmax-eligible	0.00937%	10,668
East Asian	0.00223%	44,858
South Asian	0.0022%	45,527

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: ABCC8
Protein: p.Ala726Thr
Coding: c.2176G>A
MANE Select: NM_000352
dbSNP: rs138687850
Type: single nucleotide variant
Location: chr11:17427095 (GRCh38)
Gene constraint: LOEUF 0.829 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.56 · 8 PDB
Residue 726: an α-helix; the abc transporter 1 domain

Full ABCC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pulmonary arterial hypertension — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: type 2 diabetes mellitus hypoglycemia, leucine-induced hyperinsulinemic hypoglycemia, familial, 1 diabetes mellitus, transient neonatal, 2 diabetes mellitus, permanent neonatal 3 permanent neonatal diabetes mellitus

For Idiopathic/heritable pulmonary arterial hypertension (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

ABCC8 p.Ala726Ser Uncertain significance ★★ ⚠ same residue
ABCC8 p.Ala726= Likely benign ★ same residue
ABCC8 c.1176+2T>C Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.1333-1013A>G Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.148+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.148+2T>G Likely pathogenic ★★ same condition
ABCC8 c.1630+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.1630+1G>T 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/abcc8-p-ala726thr (accessed [today's date]).

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