Is PRKDC p.Pro2457Ser (c.7369C>T) pathogenic?

PRKDC p.Pro2457Ser (c.7369C>T) is classified Uncertain significance in PRKDC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-11). AlphaMissense: likely benign (0.0947); Very rare (popmax 0.00292%, nfe); Associated with severe combined immunodeficiency due to DNA-PKcs deficiency.

What condition is associated with PRKDC p.Pro2457Ser (c.7369C>T)?

PRKDC p.Pro2457Ser (c.7369C>T) is associated with severe combined immunodeficiency due to DNA-PKcs deficiency (ClinVar).

How common is PRKDC p.Pro2457Ser (c.7369C>T) in the general population?

PRKDC p.Pro2457Ser (c.7369C>T) is very rare (popmax 0.00292%, nfe) (gnomAD).

What do computational predictors say about PRKDC p.Pro2457Ser (c.7369C>T)?

AlphaMissense predicts likely benign (score 0.0947) — an in-silico prediction, not a clinical call.

PRKDC p.Pro2457Ser

Q: How is Severe combined immunodeficiency due to DNA-PKcs deficiency inherited?

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

c.7369C>T · rs763641731 · VCV1392487

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0947 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00292%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

severe combined immunodeficiency due to DNA-PKcs deficiency

Computational evidence

Protein change
AlphaMissense	0.0947	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -0.67, phastCons 0.46
Regional constraint	o/e 0.92	unconstrained · MANE · 63 kb · p 0.0014 · regional, not allelic
Overall
CADD	2.609	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00292% European (non-Finnish) · 34/1,164,374 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00185%

Overall 0.00214% 34/1,586,306 alleles · very rare exomes 33/1,434,160 · genomes 1/152,146 · 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: PRKDC
Protein: p.Pro2457Ser
Coding: c.7369C>T
MANE Select: NM_006904
dbSNP: rs763641731
Type: single nucleotide variant
Location: chr8:47840101 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 (gnomAD)
Residue 2457: the 'kip-binding' region; an α-helix

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

Disease context

severe combined immunodeficiency due to DNA-PKcs deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Severe combined immunodeficiency due to DNA-PKcs deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

PRKDC p.Pro2457= Conflicting classifications of pathogenicity ★ same residue
PRKDC p.Pro2457Ala Uncertain significance ★ ⚠ same residue
PRKDC p.Pro2457Arg Uncertain significance ★ ⚠ same residue
PRKDC p.Pro2457Leu Uncertain significance ★ ⚠ same residue
PRKDC c.2259+6C>T Uncertain significance ★★ same condition
PRKDC c.3464+4G>A Uncertain significance ★★ same condition
PRKDC c.5235+6T>C Uncertain significance ★★ same condition
PRKDC c.5919+5G>A 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/prkdc-p-pro2457ser (accessed [today's date]).

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