Is DRC9 p.Leu75= (c.225C>G) pathogenic?

DRC9 p.Leu75= (c.225C>G) is classified Benign in DRC9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-06-18). Common (popmax 9.44%, afr) — too common for a highly-penetrant pathogenic allele.

DRC9 p.Leu75=

Q: How common is DRC9 p.Leu75= (c.225C>G) in the general population?

DRC9 p.Leu75= (c.225C>G) is common (popmax 9.44%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.225C>G · rs34070639 · VCV783413

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 9.44%, 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 -0.32	phastCons 0.012
Overall
CADD	1.939	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.44% African / African-American · 7,077/75,002 alleles

Filtering AF 9.25% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.18%

Overall 0.501% 8,094/1,614,112 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.44%	11
Remaining individualsnot grpmax-eligible	0.595%	168
Admixed American	0.542%	185
Middle Eastern	0.379%	264
South Asian	0.0242%	4,140
European (non-Finnish)	0.0232%	4,307
East Asian	0.00223%	44,878

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: DRC9
Protein: p.Leu75=
Coding: c.225C>G
MANE Select: NM_032263
dbSNP: rs34070639
Type: single nucleotide variant
Location: chr3:197943835 (GRCh38)
Structure: AlphaFold pLDDT 72.42 · 3 PDB

Full DRC9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RPL35A p.Thr75Ser Uncertain significance ★ ⚠ same residue
RPL35A c.309+3G>C Uncertain significance ★★ same type
RPL35A c.309+4A>T Uncertain significance ★★ same type
RPL35A p.Ala12Thr Uncertain significance ★★ ⚠ same type
RPL35A p.Ala12Val Uncertain significance ★★ ⚠ same type
RPL35A p.Arg19Trp Uncertain significance ★★ ⚠ same type
RPL35A p.Arg46= Uncertain significance ★★ same type
RPL35A p.Arg76Gln 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/drc9-p-leu75 (accessed [today's date]).

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