Is HSD11B2 p.Pro399Ala (c.1195C>G) pathogenic?

HSD11B2 p.Pro399Ala (c.1195C>G) is classified Uncertain significance in HSD11B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-01). AlphaMissense: likely benign (0.0573); Very rare (popmax 0.00329%, sas); Associated with apparent mineralocorticoid excess.

What condition is associated with HSD11B2 p.Pro399Ala (c.1195C>G)?

HSD11B2 p.Pro399Ala (c.1195C>G) is associated with apparent mineralocorticoid excess (ClinVar).

How common is HSD11B2 p.Pro399Ala (c.1195C>G) in the general population?

HSD11B2 p.Pro399Ala (c.1195C>G) is very rare (popmax 0.00329%, sas) (gnomAD).

How is Apparent mineralocorticoid excess inherited?

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

What do computational predictors say about HSD11B2 p.Pro399Ala (c.1195C>G)?

AlphaMissense predicts likely benign (score 0.0573) — an in-silico prediction, not a clinical call.

HSD11B2 p.Pro399Ala

c.1195C>G · VCV3581177

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0573 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

apparent mineralocorticoid excess

Computational evidence

Protein change
AlphaMissense	0.0573	likely benign
REVEL	0.175	moderately benign-leaning
SaProt	LLR -6.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.048	GERP -4.1, phastCons 0.009
Regional constraint	o/e 0.78	unconstrained · MANE · 5,569 bp · p 1.1e-06 · regional, not allelic
Overall
CADD	11.86	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 0.00329% South Asian · 3/91,080 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000186% 3/1,610,026 alleles · very rare exomes 3/1,457,684 · genomes 0/152,342 · 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: HSD11B2
Protein: p.Pro399Ala
Coding: c.1195C>G
MANE Select: NM_000196
Type: single nucleotide variant
Location: chr16:67436980 (GRCh38)
Gene constraint: LOEUF 1.204 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.49
Residue 399: the 'disordered' region; a UniProt-annotated variant site (in ame; decreases enzyme activity)

Full HSD11B2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

apparent mineralocorticoid excess — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Apparent mineralocorticoid excess (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

HSD11B2 p.Ala328Val Likely pathogenic ★★ same condition
HSD11B2 p.Arg208His Pathogenic/Likely pathogenic ★★ same condition
HSD11B2 c.664+14C>T Uncertain significance ★★ same condition
HSD11B2 p.Ala196Thr Uncertain significance ★★ ⚠ same condition
HSD11B2 p.Ala19Val Uncertain significance ★★ ⚠ same condition
HSD11B2 p.Ala389Thr Uncertain significance ★★ ⚠ same condition
HSD11B2 p.Arg147His Uncertain significance ★★ ⚠ same condition
HSD11B2 p.Arg312His 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/hsd11b2-p-pro399ala (accessed [today's date]).

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