Is PNN p.Asp67Val (c.200A>T) pathogenic?

PNN p.Asp67Val (c.200A>T) is classified Uncertain significance in PNN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-07). AlphaMissense: likely pathogenic (0.9563); Ultra-rare (popmax 0.0429%, afr).

How common is PNN p.Asp67Val (c.200A>T) in the general population?

PNN p.Asp67Val (c.200A>T) is ultra-rare (popmax 0.0429%, afr) (gnomAD).

What do computational predictors say about PNN p.Asp67Val (c.200A>T)?

AlphaMissense predicts likely pathogenic (score 0.9563) — an in-silico prediction, not a clinical call.

PNN p.Asp67Val

c.200A>T · VCV3891082

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9563 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0429%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9563	likely pathogenic
REVEL	0.609	indeterminate
SaProt	LLR -7.01	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 2,357 bp · p 0.65 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0429% African / African-American · 32/74,602 alleles

Filtering AF 0.0311% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0272%

Overall 0.00199% 32/1,607,562 alleles · ultra-rare exomes 15/1,455,370 · genomes 17/152,192 · 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: PNN
Protein: p.Asp67Val
Coding: c.200A>T
MANE Select: NM_002687
Type: single nucleotide variant
Location: chr14:39176541 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI 0.43 (gnomAD)
Structure: AlphaFold pLDDT 58.30
Residue 67: the 'necessary for interaction with rnps1' region; the 'necessary for mediating alternative 5' splicing' region; the 'necessary for interactions with krt8, krt18 and krt19' region; the 'disordered' region

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

Similar variants

PNN c.185+10C>T Benign ★★ same type
PNN p.Arg185= Benign/Likely benign ★★ same type
PNN p.Glu526Lys Benign ★★ same type
PNN p.Ser624= Benign ★★ same type
PNN p.Ala111Thr Uncertain significance ★ ⚠ same type
PNN p.Ala343Val Uncertain significance ★ ⚠ same type
PNN p.Ala421Pro Uncertain significance ★ ⚠ same type
PNN p.Ala421Val Uncertain significance ★ ⚠ same type

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/pnn-p-asp67val (accessed [today's date]).

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