Is VDR p.Ser148= (c.444C>T) pathogenic?

VDR p.Ser148= (c.444C>T) is classified Benign/Likely benign in VDR (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-31). Low-frequency (popmax 2.15%, afr); Associated with vitamin D-dependent rickets, type 2A.

What condition is associated with VDR p.Ser148= (c.444C>T)?

VDR p.Ser148= (c.444C>T) is associated with vitamin D-dependent rickets, type 2A (ClinVar).

How common is VDR p.Ser148= (c.444C>T) in the general population?

VDR p.Ser148= (c.444C>T) is low-frequency (popmax 2.15%, afr) (gnomAD).

How is Hypocalcemic vitamin D-resistant rickets inherited?

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

VDR p.Ser148=

c.444C>T · rs2229828 · VCV791551

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.15%, afr)

Conditions

vitamin D-dependent rickets, type 2A

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 -9.3	GERP -3.2
Overall
CADD	0.975	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.15% African / African-American · 1,617/75,036 alleles

Filtering AF 2.07% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.03%

Overall 0.118% 1,899/1,614,158 alleles · low-frequency exomes 1,010/1,461,876 · genomes 889/152,282 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.15%	46
Middle Eastern	0.264%	379
Remaining individualsnot grpmax-eligible	0.163%	613
Admixed American	0.138%	723
European (non-Finnish)	0.00636%	15,734
South Asian	0.00439%	22,770
Finnishnot grpmax-eligible	0.00312%	32,004

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: VDR
Protein: p.Ser148=
Coding: c.444C>T
MANE Select: NM_000376
dbSNP: rs2229828
Type: single nucleotide variant
Location: chr12:47857522 (GRCh38)
Gene constraint: LOEUF 0.714 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.56 · 52 PDB
Residue 148: the nr lbd domain

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

Disease context

vitamin D-dependent rickets, type 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hypocalcemic vitamin D-resistant rickets (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

VDR p.Arg274His Pathogenic/Likely pathogenic ★★ ⚠ same condition
VDR p.Arg30Ter Pathogenic ★★ same condition
VDR p.Arg343Cys Likely pathogenic ★★ same condition
VDR p.Arg391His Pathogenic ★★ same condition
VDR p.Arg50Ter Pathogenic ★★ same condition
VDR p.Arg73Gln Pathogenic/Likely pathogenic ★★ same condition
VDR p.Arg73Ter Pathogenic ★★ same condition
VDR p.Tyr295Ter 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/vdr-p-ser148 (accessed [today's date]).

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