Is DLC1 p.Pro1287Ser (c.3859C>T) pathogenic?

DLC1 p.Pro1287Ser (c.3859C>T) is classified Uncertain significance in DLC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-22). AlphaMissense: likely pathogenic (0.65); Very rare (popmax 0.00144%, nfe).

How common is DLC1 p.Pro1287Ser (c.3859C>T) in the general population?

DLC1 p.Pro1287Ser (c.3859C>T) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about DLC1 p.Pro1287Ser (c.3859C>T)?

AlphaMissense predicts likely pathogenic (score 0.65) — an in-silico prediction, not a clinical call.

DLC1 p.Pro1287Ser

c.3859C>T · rs775033474 · VCV2215105

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.65 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.65	likely pathogenic
REVEL	0.401	indeterminate
SaProt	LLR -8.52	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Overall
CADD	23.9	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 0.00144% European (non-Finnish) · 17/1,180,028 alleles

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

Overall 0.00112% 18/1,613,634 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,456
European (non-Finnish)grpmax	0.00144%	69,414

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro1287Ser
Coding: c.3859C>T
MANE Select: NM_003746 · reported on NM_182643
dbSNP: rs775033474
Type: single nucleotide variant
Location: chr8:13090467 (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-pro1287ser (accessed [today's date]).

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