Is POMC p.Ser4= (c.12G>A) pathogenic?

POMC p.Ser4= (c.12G>A) is classified Likely benign in POMC (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-09-11). Very rare (popmax 0.00445%, eas); Associated with POMC-related disorder.

What condition is associated with POMC p.Ser4= (c.12G>A)?

POMC p.Ser4= (c.12G>A) is associated with POMC-related disorder (ClinVar).

How common is POMC p.Ser4= (c.12G>A) in the general population?

POMC p.Ser4= (c.12G>A) is very rare (popmax 0.00445%, eas) (gnomAD).

POMC p.Ser4=

c.12G>A · rs773178150 · VCV3036959

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

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 -1.6	GERP -3.1
Overall
CADD	8.199	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00445% East Asian · 2/44,900 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00174% 28/1,613,788 alleles · very rare exomes 27/1,461,538 · genomes 1/152,250 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,450
South Asian	0.00329%	30,361
European (non-Finnish)	0.00186%	53,639
African / African-American	0.00133%	74,930

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.Ser4=
Coding: c.12G>A
MANE Select: NM_000939
dbSNP: rs773178150
Type: single nucleotide variant
Location: chr2:25164761 (GRCh38)
Gene constraint: LOEUF 1.796 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.47 · 13 PDB

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

Disease context

POMC-related disorder

Similar variants

POMC p.Ser4Pro Uncertain significance ⚠ same residue
POMC p.Ser4Leu 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-ser4 (accessed [today's date]).

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