Is PRUNE1 p.Arg66Ter (c.196C>T) pathogenic?

PRUNE1 p.Arg66Ter (c.196C>T) is classified Pathogenic/Likely pathogenic in PRUNE1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-20). Very rare (popmax 0.00267%, afr); Associated with neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies.

How common is PRUNE1 p.Arg66Ter (c.196C>T) in the general population?

PRUNE1 p.Arg66Ter (c.196C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

PRUNE1 p.Arg66Ter

Q: What condition is associated with PRUNE1 p.Arg66Ter (c.196C>T)?

PRUNE1 p.Arg66Ter (c.196C>T) is associated with neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (ClinVar).

c.196C>T · rs137929776 · VCV430526

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies

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 3 of 8
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.49	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 3.9	GERP 0.49, 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 0.00267% African / African-American · 2/74,878 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00205% 33/1,613,268 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,439
European (non-Finnish)	0.00246%	40,668
East Asian	0.00223%	44,892
South Asian	0.0011%	91,074

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: PRUNE1
Protein: p.Arg66Ter
Coding: c.196C>T
MANE Select: NM_021222
dbSNP: rs137929776
Type: single nucleotide variant
Location: chr1:151018530 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.61

Full PRUNE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PRUNE1 p.Arg66Gln Uncertain significance ★ same residue
PRUNE1 c.132+2T>C Pathogenic ★★ same condition
PRUNE1 c.521-2A>G Pathogenic/Likely pathogenic ★★ same condition
PRUNE1 p.Arg128Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
PRUNE1 p.Asp106Asn Pathogenic/Likely pathogenic ★★ same condition
PRUNE1 p.Asp30Asn Pathogenic/Likely pathogenic ★★ same condition
PRUNE1 p.Ala39Pro Uncertain significance ★★ ⚠ same condition
PRUNE1 p.His19Arg 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/prune1-p-arg66ter (accessed [today's date]).

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