Is PRKDC p.Ser412Arg (c.1236C>G) pathogenic?

PRKDC p.Ser412Arg (c.1236C>G) is classified Uncertain significance in PRKDC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-01). AlphaMissense: likely pathogenic (0.9534); Very rare (popmax 0.00167%, amr).

How common is PRKDC p.Ser412Arg (c.1236C>G) in the general population?

PRKDC p.Ser412Arg (c.1236C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about PRKDC p.Ser412Arg (c.1236C>G)?

AlphaMissense predicts likely pathogenic (score 0.9534) — an in-silico prediction, not a clinical call.

PRKDC p.Ser412Arg

c.1236C>G · rs371084198 · VCV3225735

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9534 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.9534	likely pathogenic · top 3% in PRKDC
REVEL	0.285	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; 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 0.67	GERP -3, phastCons 0.95
Regional constraint	o/e 0.95	unconstrained · MANE · 90 kb · p 0.028 · regional, not allelic
Overall
CADD	17.15	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 0.00167% Admixed American · 1/59,994 alleles

Overall 6.2e-05% 1/1,613,824 alleles · very rare exomes 0/1,461,624 · genomes 1/152,200 · 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.Ser412Arg
Coding: c.1236C>G
MANE Select: NM_006904
dbSNP: rs371084198
Type: single nucleotide variant
Location: chr8:47936395 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 (gnomAD)
Residue 412: an α-helix

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

Similar variants

PRKDC p.Ser412= Likely benign ★★ same residue
PRKDC p.Ser412Gly Uncertain significance ★ ⚠ same residue
PRKDC c.2259+6C>T Uncertain significance ★★ same type
PRKDC c.3464+4G>A Uncertain significance ★★ same type
PRKDC c.5235+6T>C Uncertain significance ★★ same type
PRKDC c.5919+5G>A Uncertain significance ★★ same type
PRKDC p.Ala1008Val Uncertain significance ★★ ⚠ same type
PRKDC p.Ala1103Val Uncertain significance ★★ ⚠ same type

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-ser412arg (accessed [today's date]).

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