Is POMC p.Asp166= (c.498C>T) pathogenic?

POMC p.Asp166= (c.498C>T) is classified Conflicting classifications of pathogenicity in POMC (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-10-17). Very rare (popmax 0.00212%, nfe); Associated with obesity due to pro-opiomelanocortin deficiency.

What condition is associated with POMC p.Asp166= (c.498C>T)?

POMC p.Asp166= (c.498C>T) is associated with obesity due to pro-opiomelanocortin deficiency, obesity disorder (ClinVar).

How common is POMC p.Asp166= (c.498C>T) in the general population?

POMC p.Asp166= (c.498C>T) is very rare (popmax 0.00212%, nfe) (gnomAD).

POMC p.Asp166=

c.498C>T · rs760352559 · VCV895580

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Conditions

obesity due to pro-opiomelanocortin deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.17, phastCons 1
Overall
CADD	13.25	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00212% European (non-Finnish) · 25/1,177,850 alleles

Filtering AF 0.00146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00155% 25/1,608,132 alleles · very rare exomes 21/1,456,092 · genomes 4/152,040 · joint denominator

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: POMC
Protein: p.Asp166=
Coding: c.498C>T
MANE Select: NM_000939
dbSNP: rs760352559
Type: single nucleotide variant
Location: chr2:25161387 (GRCh38)
Gene constraint: LOEUF 1.796 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.47 · 13 PDB
Residue 166: the 'disordered' region

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

Disease context

obesity due to pro-opiomelanocortin deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: obesity disorder

Similar variants

POMC c.-11C>A Pathogenic ★★ same condition
POMC p.Ala164Val Uncertain significance ★★ ⚠ same condition
POMC p.Ala213Val Uncertain significance ★★ ⚠ same condition
POMC p.Arg145Cys Uncertain significance ★★ ⚠ same condition
POMC p.Arg145His Uncertain significance ★★ ⚠ same condition
POMC p.His143Gln Uncertain significance ★★ ⚠ same condition
POMC p.Ser95Gly Uncertain significance ★★ ⚠ same condition
POMC p.Thr39Met 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/pomc-p-asp166 (accessed [today's date]).

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