Is PRKDC p.Phe3542= (c.10626C>T) pathogenic?

PRKDC p.Phe3542= (c.10626C>T) is classified Benign/Likely benign in PRKDC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). Low-frequency (popmax 1.82%, afr); Associated with severe combined immunodeficiency due to DNA-PKcs deficiency.

What condition is associated with PRKDC p.Phe3542= (c.10626C>T)?

PRKDC p.Phe3542= (c.10626C>T) is associated with severe combined immunodeficiency due to DNA-PKcs deficiency (ClinVar).

How common is PRKDC p.Phe3542= (c.10626C>T) in the general population?

PRKDC p.Phe3542= (c.10626C>T) is low-frequency (popmax 1.82%, afr) (gnomAD).

PRKDC p.Phe3542=

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.10626C>T · rs8178231 · VCV380474

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.82%, afr)

Conditions

severe combined immunodeficiency due to DNA-PKcs deficiency

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 2.4	GERP -0.094, phastCons 0.99
Overall
CADD	7.105	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.82% African / African-American · 1,368/75,012 alleles

Filtering AF 1.74% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.71%

Overall 0.0977% 1,576/1,613,486 alleles · low-frequency exomes 762/1,461,218 · genomes 814/152,268 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.82%	55
Admixed American	0.177%	566
Remaining individualsnot grpmax-eligible	0.136%	735
Middle Eastern	0.0165%	6,062
South Asian	0.0033%	30,327
European (non-Finnish)	0.0011%	90,744

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.Phe3542=
Coding: c.10626C>T
MANE Select: NM_006904
dbSNP: rs8178231
Type: single nucleotide variant
Location: chr8:47794334 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 (gnomAD)

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-phe3542 (accessed [today's date]).

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