Is POMC p.Ser168= (c.504G>C) pathogenic?

POMC p.Ser168= (c.504G>C) is classified Likely benign in POMC (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-11-22). Very rare (popmax 0.00267%, afr); Associated with POMC-related disorder.

What condition is associated with POMC p.Ser168= (c.504G>C)?

POMC p.Ser168= (c.504G>C) is associated with POMC-related disorder (ClinVar).

How common is POMC p.Ser168= (c.504G>C) in the general population?

POMC p.Ser168= (c.504G>C) is very rare (popmax 0.00267%, afr) (gnomAD).

POMC p.Ser168=

c.504G>C · rs1054095367 · VCV3057553

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

POMC-related disorder

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 -0.42	GERP -2.5, phastCons 0.034
Overall
CADD	7.542	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,780 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000249% 4/1,607,046 alleles · very rare exomes 2/1,454,932 · genomes 2/152,114 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,390
Remaining individualsnot grpmax-eligible	0.00161%	62,158
South Asian	0.00111%	89,818

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.Ser168=
Coding: c.504G>C
MANE Select: NM_000939
dbSNP: rs1054095367
Type: single nucleotide variant
Location: chr2:25161381 (GRCh38)
Gene constraint: LOEUF 1.796 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.47 · 13 PDB
Residue 168: the 'disordered' region; a modified residue (phosphoserine)

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

Disease context

POMC-related disorder

Similar variants

POMC p.Ser168Pro Uncertain significance ⚠ same residue
POMC p.Ser168Leu Uncertain significance ★ ⚠ same residue
POMC p.Asn42Ser Uncertain significance ★ ⚠ same condition
POMC p.Asn91Ser Uncertain significance ★ ⚠ same condition
POMC p.Cys34Arg Uncertain significance ★ ⚠ same condition
POMC p.Ser95Asn Uncertain significance ★ ⚠ same condition
POMC p.Thr39= Conflicting classifications of pathogenicity ★ same condition
POMC c.132+5G>A 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-ser168 (accessed [today's date]).

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