Is POMC p.Pro69Ala (c.205C>G) pathogenic?

POMC p.Pro69Ala (c.205C>G) is classified Uncertain significance in POMC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely benign (0.095); Very rare (popmax 0.00136%, afr); Associated with Inborn genetic diseases.

What condition is associated with POMC p.Pro69Ala (c.205C>G)?

POMC p.Pro69Ala (c.205C>G) is associated with Inborn genetic diseases (ClinVar).

How common is POMC p.Pro69Ala (c.205C>G) in the general population?

POMC p.Pro69Ala (c.205C>G) is very rare (popmax 0.00136%, afr) (gnomAD).

What do computational predictors say about POMC p.Pro69Ala (c.205C>G)?

AlphaMissense predicts likely benign (score 0.095) — an in-silico prediction, not a clinical call.

POMC p.Pro69Ala

c.205C>G · VCV4628196

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.095 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.095	likely benign
REVEL	0.608	indeterminate
SaProt	LLR -6.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.6, phastCons 0.97
Regional constraint	o/e 1.19	unconstrained · MANE · 3,688 bp · p 0.00022 · regional, not allelic
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00136% African / African-American · 1/73,438 alleles

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

Overall 0.000191% 3/1,572,074 alleles · very rare exomes 2/1,420,098 · genomes 1/151,976 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00136%	73,438
European (non-Finnish)	0.000172%	579,945

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.Pro69Ala
Coding: c.205C>G
MANE Select: NM_000939
Type: single nucleotide variant
Location: chr2:25161680 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

POMC p.Ser94Gly Uncertain significance ★★ ⚠ same condition
POMC p.Thr252Met Uncertain significance ★★ ⚠ same condition
POMC p.Trp84Gly Uncertain significance ★★ ⚠ same condition
POMC p.Ala128Val Uncertain significance ★ ⚠ same condition
POMC p.Ala201Val Uncertain significance ★ ⚠ same condition
POMC p.Arg104Ser Uncertain significance ★ same condition
POMC p.Arg186Leu Uncertain significance ★ ⚠ same condition
POMC p.Arg25His 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-pro69ala (accessed [today's date]).

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