Is DRC7 p.Glu658Lys (c.1972G>A) pathogenic?

DRC7 p.Glu658Lys (c.1972G>A) is classified Uncertain significance in DRC7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-23). AlphaMissense: ambiguous (0.5503); Ultra-rare (popmax 0.0133%, amr).

How common is DRC7 p.Glu658Lys (c.1972G>A) in the general population?

DRC7 p.Glu658Lys (c.1972G>A) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about DRC7 p.Glu658Lys (c.1972G>A)?

AlphaMissense predicts ambiguous (score 0.5503) — an in-silico prediction, not a clinical call.

DRC7 p.Glu658Lys

c.1972G>A · VCV4244760

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5503 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5503	ambiguous
REVEL	0.145	moderately benign-leaning
SaProt	LLR -13.98	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 33 kb · p 0.0015 · regional, not allelic
Overall
CADD	29.0	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 0.0133% Admixed American · 8/59,946 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.00261% 42/1,608,472 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,493
European (non-Finnish)	0.00264%	37,945
East Asian	0.00223%	44,768
Remaining individualsnot grpmax-eligible	0.00161%	62,258
Finnishnot grpmax-eligible	0.00159%	62,792

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: DRC7
Protein: p.Glu658Lys
Coding: c.1972G>A
MANE Select: NM_001289162
Type: single nucleotide variant
Location: chr16:57726281 (GRCh38)
Gene constraint: LOEUF 0.883 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 1 PDB

Full DRC7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DRC7 p.Ala510Pro Uncertain significance ★ ⚠ same type
DRC7 p.Ala605Val Uncertain significance ★ ⚠ same type
DRC7 p.Ala629Thr Uncertain significance ★ ⚠ same type
DRC7 p.Ala65Val Uncertain significance ★ ⚠ same type
DRC7 p.Ala709Val Uncertain significance ★ ⚠ same type
DRC7 p.Ala769Val Uncertain significance ★ ⚠ same type
DRC7 p.Arg103His Uncertain significance ★ ⚠ same type
DRC7 p.Arg112His 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/drc7-p-glu658lys (accessed [today's date]).

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