Is ABCC8 p.Phe1392Val (c.4174T>G) pathogenic?

ABCC8 p.Phe1392Val (c.4174T>G) is classified Pathogenic in ABCC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2013-07-23). AlphaMissense: likely pathogenic (0.9625); Very rare (popmax 0.000171%, nfe).

How common is ABCC8 p.Phe1392Val (c.4174T>G) in the general population?

ABCC8 p.Phe1392Val (c.4174T>G) is very rare (popmax 0.000171%, nfe) (gnomAD).

What do computational predictors say about ABCC8 p.Phe1392Val (c.4174T>G)?

AlphaMissense predicts likely pathogenic (score 0.9625) — an in-silico prediction, not a clinical call.

ABCC8 p.Phe1392Val

c.4174T>G · rs587783171 · VCV157701

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9625 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000171%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9625	likely pathogenic ✓ concordant with ClinVar
REVEL	0.954	strongly pathogenic-leaning
SaProt	LLR -13.99	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 9.4	GERP 2.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	29.3	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 0.000171% European (non-Finnish) · 2/1,167,308 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000139% 2/1,437,446 alleles · very rare

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.Phe1392Val
Coding: c.4174T>G
MANE Select: NM_000352
dbSNP: rs587783171
Type: single nucleotide variant
Location: chr11:17395876 (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 1392: a turn; the abc transporter 2 domain

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

Similar variants

ABCC8 p.Phe1392Ile Likely pathogenic ★ same residue
ABCC8 c.1176+2T>C Pathogenic/Likely pathogenic ★★ same type
ABCC8 c.1333-1013A>G Pathogenic/Likely pathogenic ★★ same type
ABCC8 c.148+1G>A Pathogenic/Likely pathogenic ★★ same type
ABCC8 c.148+2T>G Likely pathogenic ★★ same type
ABCC8 c.1630+1G>A Pathogenic/Likely pathogenic ★★ same type
ABCC8 c.1630+1G>T Pathogenic ★★ same type
ABCC8 c.1817+1G>C 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/abcc8-p-phe1392val (accessed [today's date]).

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