Is DLC1 p.Arg76Lys (c.227G>A) pathogenic?

DLC1 p.Arg76Lys (c.227G>A) is classified Uncertain significance in DLC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely benign (0.0738); Very rare (popmax 0.00144%, nfe).

How common is DLC1 p.Arg76Lys (c.227G>A) in the general population?

DLC1 p.Arg76Lys (c.227G>A) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about DLC1 p.Arg76Lys (c.227G>A)?

AlphaMissense predicts likely benign (score 0.0738) — an in-silico prediction, not a clinical call.

DLC1 p.Arg76Lys

c.227G>A · rs760597783 · VCV2553250

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0738 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0738	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -5.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.4	GERP -1.4, phastCons 0.89
Overall
CADD	12.56	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00144% European (non-Finnish) · 17/1,180,002 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00112% 18/1,613,946 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00144%	69,412
African / African-American	0.00133%	74,918

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: DLC1
Protein: p.Arg76Lys
Coding: c.227G>A
MANE Select: NM_003746 · reported on NM_182643
dbSNP: rs760597783
Type: single nucleotide variant
Location: chr8:13499845 (GRCh38)
Structure: AlphaFold pLDDT 95.45 · 22 PDB
Residue 76: the 'interaction with esr1' region; a β-strand

Full DLC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DLC1 c.2991-5C>A Uncertain significance ★★ same type
DLC1 p.Ala1268Val Uncertain significance ★★ ⚠ same type
DLC1 p.Ala1278Thr Uncertain significance ★★ ⚠ same type
DLC1 p.Ala167Pro Uncertain significance ★★ ⚠ same type
DLC1 p.Ala350Val Uncertain significance ★★ ⚠ same type
DLC1 p.Ala752Gly Uncertain significance ★★ ⚠ same type
DLC1 p.Ala821Thr Uncertain significance ★★ ⚠ same type
DLC1 p.Ala821Val 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/dlc1-p-arg76lys (accessed [today's date]).

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