Is PRKCA p.Leu277= (c.831G>A) pathogenic?

PRKCA p.Leu277= (c.831G>A) is classified Benign in PRKCA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-06-17). Common (popmax 37.6%, mid) — too common for a highly-penetrant pathogenic allele.

PRKCA p.Leu277=

Q: How common is PRKCA p.Leu277= (c.831G>A) in the general population?

PRKCA p.Leu277= (c.831G>A) is common (popmax 37.6%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.831G>A · rs2227857 · VCV1295165

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 37.6%, mid) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP -0.089, phastCons 1
Overall
CADD	9.963	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 37.6% Middle Eastern · 2,263/6,012 alleles

Filtering AF 36.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 35.8%

Overall 33.9% 539,788/1,590,964 alleles · common exomes 497,127/1,439,026 · genomes 42,661/151,938 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	41.9%	2
Amishnot grpmax-eligible	41.7%	2
Middle Easterngrpmax	37.6%	3
Finnishnot grpmax-eligible	37%	3
European (non-Finnish)	35.9%	3
South Asian	35.3%	3
Remaining individualsnot grpmax-eligible	33.3%	3
Admixed American	30%	3
East Asian	12.8%	8
African / African-American	11.4%	9

Ashkenazi Jewish 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: PRKCA
Protein: p.Leu277=
Coding: c.831G>A
MANE Select: NM_002737
dbSNP: rs2227857
Type: single nucleotide variant
Location: chr17:66688960 (GRCh38)
Gene constraint: LOEUF 0.397 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.90 · 6 PDB

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

Similar variants

PRKCA p.Asn279= Benign ★★ same type
PRKCA p.Gly129= Benign ★★ same type
PRKCA p.Ala356Thr Uncertain significance ★ ⚠ same type
PRKCA p.Arg324Lys Uncertain significance ★ ⚠ same type
PRKCA p.Arg333Gln Uncertain significance ★ ⚠ same type
PRKCA p.Arg496Gly Uncertain significance ★ ⚠ same type
PRKCA p.Asn468Asp Uncertain significance ★ ⚠ same type
PRKCA p.Asn554Ser 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/prkca-p-leu277 (accessed [today's date]).

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