Is DENND4A p.Ser122Arg (c.364A>C) pathogenic?

DENND4A p.Ser122Arg (c.364A>C) is classified Uncertain significance in DENND4A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-04). AlphaMissense: likely benign (0.2383); Very rare (popmax 0.00247%, nfe).

How common is DENND4A p.Ser122Arg (c.364A>C) in the general population?

DENND4A p.Ser122Arg (c.364A>C) is very rare (popmax 0.00247%, nfe) (gnomAD).

What do computational predictors say about DENND4A p.Ser122Arg (c.364A>C)?

AlphaMissense predicts likely benign (score 0.2383) — an in-silico prediction, not a clinical call.

DENND4A p.Ser122Arg

c.364A>C · rs759592960 · VCV2269229

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2383 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00247%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2383	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -5.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP -2.8, phastCons 0.89
Regional constraint	o/e 0.76	unconstrained · MANE · 54 kb · p 1.6e-13 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00247% European (non-Finnish) · 29/1,172,190 alleles

Filtering AF 0.00174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0015%

Overall 0.00207% 30/1,448,972 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00247%	40,420
African / African-American	0.00134%	74,838

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.Ser122Arg
Coding: c.364A>C
MANE Select: NM_001320835
dbSNP: rs759592960
Type: single nucleotide variant
Location: chr15:65752576 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.22
Residue 122: the mabp 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-ser122arg (accessed [today's date]).

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