Is DENND4A p.Leu1124Pro (c.3371T>C) pathogenic?

DENND4A p.Leu1124Pro (c.3371T>C) is classified Uncertain significance in DENND4A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: ambiguous (0.4776); Very rare (popmax 0.00133%, afr).

How common is DENND4A p.Leu1124Pro (c.3371T>C) in the general population?

DENND4A p.Leu1124Pro (c.3371T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about DENND4A p.Leu1124Pro (c.3371T>C)?

AlphaMissense predicts ambiguous (score 0.4776) — an in-silico prediction, not a clinical call.

DENND4A p.Leu1124Pro

c.3371T>C · VCV4659525

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4776 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4776	ambiguous
REVEL	0.191	benign-leaning
SaProt	LLR -7.75	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 31 kb · p 0.0012 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L1080P vs ClinVar L1124P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,918 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000806% 13/1,613,286 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,918
European (non-Finnish)	0.00102%	98,304

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.Leu1124Pro
Coding: c.3371T>C
MANE Select: NM_001320835
Type: single nucleotide variant
Location: chr15:65691223 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.22

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

Similar variants

DENND4A p.Leu1124Phe Uncertain significance ★ ⚠ same residue
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

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-leu1124pro (accessed [today's date]).

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