Is DNER p.Pro180= (c.540G>A) pathogenic?

DNER p.Pro180= (c.540G>A) is classified Benign in DNER (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-07-26). Common (popmax 5.47%, afr) — too common for a highly-penetrant pathogenic allele.

DNER p.Pro180=

Q: How common is DNER p.Pro180= (c.540G>A) in the general population?

DNER p.Pro180= (c.540G>A) is common (popmax 5.47%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.540G>A · rs146704189 · VCV790517

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 5.47%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.5	GERP -3.9
Overall
CADD	8.028	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.47% African / African-American · 4,106/75,048 alleles

Filtering AF 5.33% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.27%

Overall 0.301% 4,866/1,614,134 alleles · common exomes 2,509/1,461,830 · genomes 2,357/152,304 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.47%	18
Middle Eastern	0.577%	173
Admixed American	0.435%	230
Remaining individualsnot grpmax-eligible	0.389%	257
European (non-Finnish)	0.0176%	5,673
South Asian	0.0132%	7,588
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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.Pro180=
Coding: c.540G>A
MANE Select: NM_139072
dbSNP: rs146704189
Type: single nucleotide variant
Location: chr2:229591625 (GRCh38)
Gene constraint: LOEUF 0.561 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 70.51

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

Similar variants

DNER c.586-10C>T Benign ★★ same type
DNER p.Arg698= 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
DNER p.Ala234Thr Uncertain significance ★ ⚠ same type
DNER p.Ala362Thr 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-pro180 (accessed [today's date]).

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