Is PNPT1 p.Arg464= (c.1390C>A) pathogenic?

PNPT1 p.Arg464= (c.1390C>A) is classified Benign in PNPT1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Common (popmax 55.9%, mid) — too common for a highly-penetrant pathogenic allele; Associated with combined oxidative phosphorylation defect type 13.

What condition is associated with PNPT1 p.Arg464= (c.1390C>A)?

PNPT1 p.Arg464= (c.1390C>A) is associated with combined oxidative phosphorylation defect type 13, autosomal recessive nonsyndromic hearing loss 70 (ClinVar).

PNPT1 p.Arg464=

Q: How common is PNPT1 p.Arg464= (c.1390C>A) in the general population?

PNPT1 p.Arg464= (c.1390C>A) is common (popmax 55.9%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Combined oxidative phosphorylation defect type 13 inherited?

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

c.1390C>A · rs2627765 · VCV138737

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 55.9%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

combined oxidative phosphorylation defect type 13

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 6.2	GERP -0.57, phastCons 1
Overall
CADD	11.91	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 55.9% Middle Eastern · 3,367/6,028 alleles

Filtering AF 55.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 55.5%

Overall 52.3% 843,175/1,612,156 alleles · common exomes 769,922/1,460,290 · genomes 73,253/151,866 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	61.6%	2
Middle Easterngrpmax	55.9%	2
European (non-Finnish)	55.7%	2
Ashkenazi Jewishnot grpmax-eligible	54.9%	2
Remaining individualsnot grpmax-eligible	50.8%	2
Admixed American	47.8%	2
Amishnot grpmax-eligible	38.9%	3
South Asian	37.3%	3
African / African-American	34%	3
East Asian	16.7%	6

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: PNPT1
Protein: p.Arg464=
Coding: c.1390C>A
MANE Select: NM_033109
dbSNP: rs2627765
Type: single nucleotide variant
Location: chr2:55656182 (GRCh38)
Gene constraint: LOEUF 0.64 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.46 · 11 PDB

Full PNPT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

combined oxidative phosphorylation defect type 13 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive nonsyndromic hearing loss 70

For Combined oxidative phosphorylation defect type 13 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

PNPT1 p.Arg464Ter Pathogenic ★★ same residue
PNPT1 p.Arg464Gln Uncertain significance ★ ⚠ same residue
PNPT1 c.1906+1G>A Likely pathogenic ★★ same condition
PNPT1 p.Ala507Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
PNPT1 p.Ala510Pro Pathogenic/Likely pathogenic ★★ same condition
PNPT1 p.Arg132Ter Pathogenic/Likely pathogenic ★★ same condition
PNPT1 p.Arg136His Pathogenic/Likely pathogenic ★★ same condition
PNPT1 p.Arg192Ter 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/pnpt1-p-arg464 (accessed [today's date]).

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