Is DENND5A p.Met726Val (c.2176A>G) pathogenic?

DENND5A p.Met726Val (c.2176A>G) is classified Uncertain significance in DENND5A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-11). AlphaMissense: likely benign (0.0697); Very rare (popmax 0.00667%, afr).

How common is DENND5A p.Met726Val (c.2176A>G) in the general population?

DENND5A p.Met726Val (c.2176A>G) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about DENND5A p.Met726Val (c.2176A>G)?

AlphaMissense predicts likely benign (score 0.0697) — an in-silico prediction, not a clinical call.

DENND5A p.Met726Val

c.2176A>G · rs754451263 · VCV1948919

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0697 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0697	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -5.99	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 2.9	phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 12 kb · p 0.47 · regional, not allelic
Overall
CADD	21.3	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 0.00667% African / African-American · 5/74,930 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00229% 37/1,614,036 alleles · very rare exomes 33/1,461,830 · genomes 4/152,206 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,986
European (non-Finnish)	0.00246%	40,690
East Asian	0.00223%	44,896
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,092

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.Met726Val
Coding: c.2176A>G
MANE Select: NM_015213
dbSNP: rs754451263
Type: single nucleotide variant
Location: chr11:9165943 (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

Similar variants

DENND5A c.949+1G>A Likely pathogenic ★★ same type
DENND5A p.Arg772Ter Pathogenic/Likely pathogenic ★★ same type
DENND5A p.Ala355Pro Uncertain significance ★★ ⚠ same type
DENND5A p.Arg1159Trp Uncertain significance ★★ ⚠ same type
DENND5A p.Arg1265His Uncertain significance ★★ ⚠ same type
DENND5A p.Arg190His Uncertain significance ★★ ⚠ same type
DENND5A p.Arg198Leu Uncertain significance ★★ same type
DENND5A p.Arg198Trp 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/dennd5a-p-met726val (accessed [today's date]).

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