Is PDSS1 p.Arg76= (c.228G>C) pathogenic?

PDSS1 p.Arg76= (c.228G>C) is classified Uncertain significance in PDSS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-28). Very rare (popmax 0.005%, amr); Associated with deafness-encephaloneuropathy-obesity-valvulopathy syndrome.

What condition is associated with PDSS1 p.Arg76= (c.228G>C)?

PDSS1 p.Arg76= (c.228G>C) is associated with deafness-encephaloneuropathy-obesity-valvulopathy syndrome (ClinVar).

How common is PDSS1 p.Arg76= (c.228G>C) in the general population?

PDSS1 p.Arg76= (c.228G>C) is very rare (popmax 0.005%, amr) (gnomAD).

PDSS1 p.Arg76=

Q: How is Deafness-encephaloneuropathy-obesity-valvulopathy syndrome inherited?

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

c.228G>C · rs1371465378 · VCV1901671

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

deafness-encephaloneuropathy-obesity-valvulopathy syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.1	GERP -0.2, phastCons 1
Overall
CADD	15.75	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,952 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000189% 3/1,588,566 alleles · very rare exomes 3/1,436,514 · genomes 0/152,052 · 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: PDSS1
Protein: p.Arg76=
Coding: c.228G>C
MANE Select: NM_014317
dbSNP: rs1371465378
Type: single nucleotide variant
Location: chr10:26705286 (GRCh38)
Gene constraint: LOEUF 1.163 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.45

Full PDSS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

deafness-encephaloneuropathy-obesity-valvulopathy syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Deafness-encephaloneuropathy-obesity-valvulopathy syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

PDSS1 p.Arg76Trp Uncertain significance ★★ ⚠ same residue
PDSS1 p.Arg221Ter Likely pathogenic ★★ same condition
PDSS1 p.Trp6Ter Likely pathogenic ★★ same condition
PDSS1 c.129+5G>C Uncertain significance ★★ same condition
PDSS1 p.Ala268Thr Uncertain significance ★★ ⚠ same condition
PDSS1 p.Ala380Thr Uncertain significance ★★ ⚠ same condition
PDSS1 p.Arg146Gln Uncertain significance ★★ ⚠ same condition
PDSS1 p.Arg163His 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/pdss1-p-arg76 (accessed [today's date]).

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