Is DNER p.Pro309Leu (c.926C>T) pathogenic?

DNER p.Pro309Leu (c.926C>T) is classified Uncertain significance in DNER (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely benign (0.0806); Rare (popmax 0.491%, afr).

How common is DNER p.Pro309Leu (c.926C>T) in the general population?

DNER p.Pro309Leu (c.926C>T) is rare (popmax 0.491%, afr) (gnomAD).

What do computational predictors say about DNER p.Pro309Leu (c.926C>T)?

AlphaMissense predicts likely benign (score 0.0806) — an in-silico prediction, not a clinical call.

DNER p.Pro309Leu

c.926C>T · VCV4243399

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0806 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.491%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0806	likely benign
REVEL	0.28	benign-leaning
SaProt	LLR -6.66	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 1.5	GERP -1.4, phastCons 0.84
Regional constraint	o/e 0.94	unconstrained · MANE · 356 kb · p 0.066 · regional, not allelic
Overall
CADD	18.42	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 0.491% African / African-American · 368/75,014 alleles

Filtering AF 0.449% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.433%

Overall 0.0268% 433/1,614,046 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.491%	204
Middle Eastern	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.0336%	2,976
Admixed American	0.03%	3,334
East Asian	0.0134%	7,477
European (non-Finnish)	0.00136%	73,751
South Asian	0.0011%	91,074

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: DNER
Protein: p.Pro309Leu
Coding: c.926C>T
MANE Select: NM_139072
Type: single nucleotide variant
Location: chr2:229547014 (GRCh38)
Gene constraint: LOEUF 0.561 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 70.51
Residue 309: the egf-like 3 domain

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

Similar variants

DNER p.Pro309Ser Uncertain significance ★ ⚠ same residue
DNER c.586-10C>T Benign ★★ same type
DNER p.Arg698= Benign ★★ same type
DNER p.Pro180= Benign ★★ same type
DNER p.Thr142Ile Benign ★★ same type
DNER p.Ala11Val Uncertain significance ★ ⚠ same type
DNER p.Ala171Thr Uncertain significance ★ ⚠ same type
DNER p.Ala205Thr 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/dner-p-pro309leu (accessed [today's date]).

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