Is DENND4A p.Pro227Ser (c.679C>T) pathogenic?

DENND4A p.Pro227Ser (c.679C>T) is classified Uncertain significance in DENND4A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-18). AlphaMissense: likely pathogenic (0.6382); Ultra-rare (popmax 0.0101%, amr).

How common is DENND4A p.Pro227Ser (c.679C>T) in the general population?

DENND4A p.Pro227Ser (c.679C>T) is ultra-rare (popmax 0.0101%, amr) (gnomAD).

What do computational predictors say about DENND4A p.Pro227Ser (c.679C>T)?

AlphaMissense predicts likely pathogenic (score 0.6382) — an in-silico prediction, not a clinical call.

DENND4A p.Pro227Ser

c.679C>T · VCV4659510

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6382 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0101%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6382	likely pathogenic
REVEL	0.146	moderately benign-leaning
SaProt	LLR -11.08	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 54 kb · p 1.6e-13 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0101% Admixed American · 6/59,474 alleles

Filtering AF 0.00432% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00297%

Overall 0.000745% 12/1,609,872 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0101%	9,912
Finnishnot grpmax-eligible	0.00313%	31,969
Remaining individualsnot grpmax-eligible	0.00161%	62,232
European (non-Finnish)	0.000255%	392,819

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: DENND4A
Protein: p.Pro227Ser
Coding: c.679C>T
MANE Select: NM_001320835
Type: single nucleotide variant
Location: chr15:65738828 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.22
Residue 227: the udenn domain

Full DENND4A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DENND4A p.Ser696Arg Likely pathogenic ★ ⚠ same type
DENND4A p.Ala1108Glu Uncertain significance ★ ⚠ same type
DENND4A p.Ala1244Gly Uncertain significance ★ ⚠ same type
DENND4A p.Ala1476Gly Uncertain significance ★ ⚠ same type
DENND4A p.Ala1585Ser Uncertain significance ★ ⚠ same type
DENND4A p.Ala1619Pro Uncertain significance ★ ⚠ same type
DENND4A p.Ala324Gly Uncertain significance ★ ⚠ same type
DENND4A p.Ala596Pro 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/dennd4a-p-pro227ser (accessed [today's date]).

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