Is PRKDC p.Pro494Ala (c.1480C>G) pathogenic?

PRKDC p.Pro494Ala (c.1480C>G) is classified Uncertain significance in PRKDC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-01-07). AlphaMissense: likely benign (0.1065); Ultra-rare (popmax 0.0211%, sas); Associated with severe combined immunodeficiency due to DNA-PKcs deficiency.

What condition is associated with PRKDC p.Pro494Ala (c.1480C>G)?

PRKDC p.Pro494Ala (c.1480C>G) is associated with severe combined immunodeficiency due to DNA-PKcs deficiency (ClinVar).

How common is PRKDC p.Pro494Ala (c.1480C>G) in the general population?

PRKDC p.Pro494Ala (c.1480C>G) is ultra-rare (popmax 0.0211%, sas) (gnomAD).

What do computational predictors say about PRKDC p.Pro494Ala (c.1480C>G)?

AlphaMissense predicts likely benign (score 0.1065) — an in-silico prediction, not a clinical call.

PRKDC p.Pro494Ala

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.1480C>G · rs771708028 · VCV1052141

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1065 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0211%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

severe combined immunodeficiency due to DNA-PKcs deficiency

Computational evidence

Protein change
AlphaMissense	0.1065	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.4	GERP 0.64, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 90 kb · p 0.028 · regional, not allelic
Overall
CADD	22.5	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 0.0211% South Asian · 17/80,474 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.011%

Overall 0.00335% 51/1,523,676 alleles · ultra-rare exomes 47/1,371,876 · genomes 4/151,800 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0487%	2,054
South Asiangrpmax	0.0211%	4,734
African / African-American	0.00139%	72,086
European (non-Finnish)	0.000355%	281,711

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: PRKDC
Protein: p.Pro494Ala
Coding: c.1480C>G
MANE Select: NM_006904
dbSNP: rs771708028
Type: single nucleotide variant
Location: chr8:47935026 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 (gnomAD)
Residue 494: 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-pro494ala (accessed [today's date]).

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