Is DRC9 p.Glu257Lys (c.769G>A) pathogenic?

DRC9 p.Glu257Lys (c.769G>A) is classified Uncertain significance in DRC9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-29). AlphaMissense: ambiguous (0.5555); Very rare (popmax 0.00666%, amr).

How common is DRC9 p.Glu257Lys (c.769G>A) in the general population?

DRC9 p.Glu257Lys (c.769G>A) is very rare (popmax 0.00666%, amr) (gnomAD).

What do computational predictors say about DRC9 p.Glu257Lys (c.769G>A)?

AlphaMissense predicts ambiguous (score 0.5555) — an in-silico prediction, not a clinical call.

DRC9 p.Glu257Lys

c.769G>A · rs1340162657 · VCV3110462

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5555 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5555	ambiguous
REVEL	0.238	benign-leaning
SaProt	LLR -6.10	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.4	phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 56 kb · p 0.19 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00666% Admixed American · 4/60,022 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000274% 4/1,461,832 alleles · very rare

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.Glu257Lys
Coding: c.769G>A
MANE Select: NM_032263
dbSNP: rs1340162657
Type: single nucleotide variant
Location: chr3:197914000 (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 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
RPL35A p.Arg85Gly 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-glu257lys (accessed [today's date]).

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