Is DLC1 p.Leu258= (c.774G>A) pathogenic?

DLC1 p.Leu258= (c.774G>A) is classified Benign/Likely benign in DLC1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-01). Common (popmax 5.66%, mid) — too common for a highly-penetrant pathogenic allele.

DLC1 p.Leu258=

Q: How common is DLC1 p.Leu258= (c.774G>A) in the general population?

DLC1 p.Leu258= (c.774G>A) is common (popmax 5.66%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.774G>A · rs62637614 · VCV1280137

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 5.66%, mid) — 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 -0.34	GERP -4.6
Overall
CADD	0.358	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.66% Middle Eastern · 343/6,062 alleles

Filtering AF 5.28% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.23%

Overall 2.54% 41,067/1,614,076 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	5.66%	18
African / African-American	5.42%	18
South Asian	3.13%	32
European (non-Finnish)	2.57%	39
Remaining individualsnot grpmax-eligible	2.52%	40
Ashkenazi Jewishnot grpmax-eligible	1.73%	58
Admixed American	1.49%	67
Finnishnot grpmax-eligible	0.82%	122
Amishnot grpmax-eligible	0.219%	456
East Asian	0.0156%	6,409

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.Leu258=
Coding: c.774G>A
MANE Select: NM_003746 · reported on NM_182643
dbSNP: rs62637614
Type: single nucleotide variant
Location: chr8:13499298 (GRCh38)
Structure: AlphaFold pLDDT 95.45 · 22 PDB

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-leu258 (accessed [today's date]).

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