Is HSD3B7 p.Pro48Arg (c.143C>G) pathogenic?

HSD3B7 p.Pro48Arg (c.143C>G) is classified Uncertain significance in HSD3B7 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-03). AlphaMissense: likely benign (0.0956); Very rare (popmax 0.00133%, afr); Associated with congenital bile acid synthesis defect 1.

What condition is associated with HSD3B7 p.Pro48Arg (c.143C>G)?

HSD3B7 p.Pro48Arg (c.143C>G) is associated with congenital bile acid synthesis defect 1 (ClinVar).

How common is HSD3B7 p.Pro48Arg (c.143C>G) in the general population?

HSD3B7 p.Pro48Arg (c.143C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Congenital bile acid synthesis defect type 1 inherited?

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

What do computational predictors say about HSD3B7 p.Pro48Arg (c.143C>G)?

AlphaMissense predicts likely benign (score 0.0956) — an in-silico prediction, not a clinical call.

HSD3B7 p.Pro48Arg

c.143C>G · rs2056463300 · VCV2432539

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0956 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital bile acid synthesis defect 1

Computational evidence

Protein change
AlphaMissense	0.0956	likely benign
REVEL	0.282	benign-leaning
SaProt	LLR -9.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP 2.3, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 2,521 bp · p 0.00046 · regional, not allelic
Overall
CADD	21.4	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 0.00133% African / African-American · 1/74,910 alleles

Overall 0.000125% 2/1,602,588 alleles · very rare exomes 2/1,450,220 · genomes 0/152,368 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	61,974
African / African-Americangrpmax	0.00133%	74,910

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: HSD3B7
Protein: p.Pro48Arg
Coding: c.143C>G
MANE Select: NM_025193
dbSNP: rs2056463300
Type: single nucleotide variant
Location: chr16:30985801 (GRCh38)
Gene constraint: LOEUF 1.411 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 94.01

Full HSD3B7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital bile acid synthesis defect 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital bile acid synthesis defect type 1 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

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HSD3B7 p.Tyr344Cys Uncertain significance ★★ ⚠ same condition
HSD3B7 p.Arg356= Benign ★★ same condition
HSD3B7 p.Thr250Ala Benign ★★ same condition
HSD3B7 c.322+1G>T Likely pathogenic ★ same condition
HSD3B7 c.323-1G>A Likely pathogenic ★ same condition
HSD3B7 c.431+2T>C Likely pathogenic ★ 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/hsd3b7-p-pro48arg (accessed [today's date]).

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