Is DENND5A p.Pro12= (c.36C>T) pathogenic?

DENND5A p.Pro12= (c.36C>T) is classified Benign/Likely benign in DENND5A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). Low-frequency (popmax 2.55%, afr); Associated with developmental and epileptic encephalopathy, 49.

What condition is associated with DENND5A p.Pro12= (c.36C>T)?

DENND5A p.Pro12= (c.36C>T) is associated with developmental and epileptic encephalopathy, 49 (ClinVar).

How common is DENND5A p.Pro12= (c.36C>T) in the general population?

DENND5A p.Pro12= (c.36C>T) is low-frequency (popmax 2.55%, afr) (gnomAD).

DENND5A p.Pro12=

c.36C>T · rs76048646 · VCV1529145

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.55%, afr)

Conditions

developmental and epileptic encephalopathy, 49

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 6	phastCons 1
Overall
CADD	15.03	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.55% African / African-American · 1,807/70,968 alleles

Filtering AF 2.45% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.41%

Overall 0.128% 2,008/1,565,912 alleles · low-frequency exomes 893/1,414,042 · genomes 1,115/151,870 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.55%	39
Admixed American	0.137%	727
Remaining individualsnot grpmax-eligible	0.121%	829
Middle Eastern	0.06%	1,667
European (non-Finnish)	0.00423%	23,664

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: DENND5A
Protein: p.Pro12=
Coding: c.36C>T
MANE Select: NM_015213
dbSNP: rs76048646
Type: single nucleotide variant
Location: chr11:9265034 (GRCh38)
Gene constraint: LOEUF 0.574 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.74

Full DENND5A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy, 49 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DENND5A c.949+1G>A Likely pathogenic ★★ same condition
DENND5A p.Arg772Ter Pathogenic/Likely pathogenic ★★ same condition
DENND5A p.Arg471Trp Uncertain significance ★★ ⚠ same condition
DENND5A p.Arg517Gln Uncertain significance ★★ ⚠ same condition
DENND5A p.Asn495His Uncertain significance ★★ ⚠ same condition
DENND5A p.Asp647Gly Uncertain significance ★★ ⚠ same condition
DENND5A p.Lys485Glu Uncertain significance ★★ ⚠ same condition
DENND5A p.Ser684Gly 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/dennd5a-p-pro12 (accessed [today's date]).

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