Is PRKDC p.Ala3622Pro (c.10864G>C) pathogenic?

PRKDC p.Ala3622Pro (c.10864G>C) is classified Uncertain significance in PRKDC (ClinVar, Single submitter, 1 submitter; last evaluated 2020-06-29). AlphaMissense: ambiguous (0.3579); Very rare (popmax 0.00446%, eas); Associated with severe combined immunodeficiency due to DNA-PKcs deficiency.

What condition is associated with PRKDC p.Ala3622Pro (c.10864G>C)?

PRKDC p.Ala3622Pro (c.10864G>C) is associated with severe combined immunodeficiency due to DNA-PKcs deficiency (ClinVar).

How common is PRKDC p.Ala3622Pro (c.10864G>C) in the general population?

PRKDC p.Ala3622Pro (c.10864G>C) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about PRKDC p.Ala3622Pro (c.10864G>C)?

AlphaMissense predicts ambiguous (score 0.3579) — an in-silico prediction, not a clinical call.

PRKDC p.Ala3622Pro

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.10864G>C · rs545479220 · VCV1045857

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3579 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

severe combined immunodeficiency due to DNA-PKcs deficiency

Computational evidence

Protein change
AlphaMissense	0.3579	ambiguous
REVEL	0.059	moderately benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.8	GERP 1.1, phastCons 0.51
Regional constraint	o/e 0.75	unconstrained · MANE · 25 kb · p 7.5e-15 · regional, not allelic
Overall
CADD	21.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,844 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000186% 3/1,611,760 alleles · very rare exomes 2/1,459,464 · genomes 1/152,296 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,422
Remaining individualsnot grpmax-eligible	0.0016%	62,376

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.Ala3622Pro
Coding: c.10864G>C
MANE Select: NM_006904
dbSNP: rs545479220
Type: single nucleotide variant
Location: chr8:47788944 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 (gnomAD)
Residue 3622: 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 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
PRKDC p.Ala1008Val Uncertain significance ★★ ⚠ same condition
PRKDC p.Ala1103Val Uncertain significance ★★ ⚠ same condition
PRKDC p.Ala1130Ser Uncertain significance ★★ ⚠ same condition
PRKDC p.Ala1130Thr 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-ala3622pro (accessed [today's date]).

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