Is GCGR p.Pro86Ser (c.256C>T) pathogenic?

GCGR p.Pro86Ser (c.256C>T) is classified Pathogenic in GCGR (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-04-22). AlphaMissense: likely pathogenic (0.7045); Very rare (popmax 0.00244%, eas); Associated with GCGR-related hyperglucagonemia.

What condition is associated with GCGR p.Pro86Ser (c.256C>T)?

GCGR p.Pro86Ser (c.256C>T) is associated with GCGR-related hyperglucagonemia (ClinVar).

How common is GCGR p.Pro86Ser (c.256C>T) in the general population?

GCGR p.Pro86Ser (c.256C>T) is very rare (popmax 0.00244%, eas) (gnomAD).

How is GCGR-related hyperglucagonemia inherited?

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

What do computational predictors say about GCGR p.Pro86Ser (c.256C>T)?

AlphaMissense predicts likely pathogenic (score 0.7045) — an in-silico prediction, not a clinical call.

GCGR p.Pro86Ser

c.256C>T · rs2143128666 · VCV1064733

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7045 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00244%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

GCGR-related hyperglucagonemia

Computational evidence

Protein change
AlphaMissense	0.7045	likely pathogenic ✓ concordant with ClinVar
REVEL	0.444	indeterminate
SaProt	LLR -10.42	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 4,667 bp · p 0.087 · regional, not allelic
Overall
CADD	30.0	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 0.00244% East Asian · 1/40,920 alleles

Overall 0.00013% 2/1,536,620 alleles · very rare exomes 2/1,384,382 · genomes 0/152,238 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00244%	40,920
European (non-Finnish)	8.72e-05%	1,146,826

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: GCGR
Protein: p.Pro86Ser
Coding: c.256C>T
MANE Select: NM_000160
dbSNP: rs2143128666
Type: single nucleotide variant
Location: chr17:81810917 (GRCh38)
Gene constraint: LOEUF 1.018 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.56 · 28 PDB
Residue 86: a UniProt-annotated variant site (in mvah; abolishes glucagon binding); a turn

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

Disease context

GCGR-related hyperglucagonemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For GCGR-related hyperglucagonemia (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult

Similar variants

GCGR p.Asp63Asn Uncertain significance ★ ⚠ same condition
GCGR p.Gly234Asp Uncertain significance ★ ⚠ same condition
GCGR c.879-1G>A Pathogenic same condition
GCGR p.Phe320del Uncertain significance ★★ same condition
GCGR c.1176+1_1176+7del Likely pathogenic ★ same condition
GCGR p.Ala155fs Pathogenic ★ same condition
GCGR p.Met301fs Likely pathogenic ★ same condition
GCGR p.Trp83fs 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/gcgr-p-pro86ser (accessed [today's date]).

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