Is PDSS1 p.Arg221Ter (c.661C>T) pathogenic?

PDSS1 p.Arg221Ter (c.661C>T) is classified Likely pathogenic in PDSS1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-30). Very rare (popmax 0.00167%, amr); Associated with deafness-encephaloneuropathy-obesity-valvulopathy syndrome.

What condition is associated with PDSS1 p.Arg221Ter (c.661C>T)?

PDSS1 p.Arg221Ter (c.661C>T) is associated with deafness-encephaloneuropathy-obesity-valvulopathy syndrome (ClinVar).

How common is PDSS1 p.Arg221Ter (c.661C>T) in the general population?

PDSS1 p.Arg221Ter (c.661C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

PDSS1 p.Arg221Ter

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

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

c.661C>T · rs767499454 · VCV2499451

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

deafness-encephaloneuropathy-obesity-valvulopathy syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 12
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.7	GERP 0.78, phastCons 1
Overall
CADD	40.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,998 alleles

Filtering AF 0.000543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000429%

Overall 0.000868% 14/1,613,390 alleles · very rare exomes 12/1,461,246 · genomes 2/152,144 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,998
Remaining individualsnot grpmax-eligible	0.0016%	62,462
European (non-Finnish)	0.00102%	98,290

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.Arg221Ter
Coding: c.661C>T
MANE Select: NM_014317
dbSNP: rs767499454
Type: single nucleotide variant
Location: chr10:26723857 (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.Arg221Gln Uncertain significance ★★ ⚠ same residue
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
PDSS1 p.Arg240His 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-arg221ter (accessed [today's date]).

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