Is DRC4 c.756+252C>G pathogenic?

DRC4 c.756+252C>G is classified Benign in DRC4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-11-11). Common (popmax 46%, nfe) — too common for a highly-penetrant pathogenic allele.

DRC4 c.756+252C>G

Q: How common is DRC4 c.756+252C>G in the general population?

DRC4 c.756+252C>G is common (popmax 46%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs4374173 · VCV1274591

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 46%, nfe) — 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
Splice region	donor +252	deep intronic (+252 nt into the intron)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.13
Overall
CADD	2.033	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 46% European (non-Finnish) · 160,151/347,898 alleles

Filtering AF 45.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 45.8%

Overall 40.3% 253,851/629,744 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	54.6%	2
Amishnot grpmax-eligible	47.3%	2
European (non-Finnish)grpmax	46%	2
Remaining individualsnot grpmax-eligible	41.8%	2
Middle Eastern	40.8%	2
Finnishnot grpmax-eligible	36.3%	3
Admixed American	34.4%	3
African / African-American	34.2%	3
South Asian	29.1%	3
East Asian	13.8%	7

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: DRC4
Coding: c.756+252C>G
MANE Select: NM_001481
dbSNP: rs4374173
Type: single nucleotide variant
Location: chr16:90036838 (GRCh38)
Structure: AlphaFold pLDDT 85.12 · 1 PDB

Full DRC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DRC4 c.495+1G>T Likely pathogenic ★★ same type
DRC4 p.Gln357Ter Pathogenic ★★ same type
DRC4 p.Ala280Thr Uncertain significance ★★ ⚠ same type
DRC4 p.Ala460Pro Uncertain significance ★★ ⚠ same type
DRC4 p.Arg143Trp Uncertain significance ★★ ⚠ same type
DRC4 p.Arg164Trp Uncertain significance ★★ ⚠ same type
DRC4 p.Arg203Gln Uncertain significance ★★ ⚠ same type
DRC4 p.Arg278Cys 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/drc4-c-756-plus-252c-g (accessed [today's date]).

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