Is CABLES2 p.Leu103= (c.309G>A) pathogenic?

CABLES2 p.Leu103= (c.309G>A) is classified Benign in CABLES2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-07-17). Common (popmax 24.3%, mid) — too common for a highly-penetrant pathogenic allele.

CABLES2 p.Leu103=

Q: How common is CABLES2 p.Leu103= (c.309G>A) in the general population?

CABLES2 p.Leu103= (c.309G>A) is common (popmax 24.3%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.309G>A · rs146975578 · VCV1257314

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 24.3%, 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 0.053	GERP 0.75, phastCons 0.93
Overall
CADD	13.75	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 24.3% Middle Eastern · 751/3,088 alleles

Filtering AF 22.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 22.3%

Overall 18.2% 220,128/1,210,908 alleles · common exomes 192,746/1,059,172 · genomes 27,382/151,736 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	45.4%	2
Middle Easterngrpmax	24.3%	4
Ashkenazi Jewishnot grpmax-eligible	24.2%	4
African / African-American	19.8%	5
European (non-Finnish)	19%	5
Remaining individualsnot grpmax-eligible	17.9%	6
Admixed American	16.7%	6
Finnishnot grpmax-eligible	14.9%	7
South Asian	4.33%	23
East Asian	0.0432%	2,316

Amish 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: CABLES2
Protein: p.Leu103=
Coding: c.309G>A
MANE Select: NM_031215
dbSNP: rs146975578
Type: single nucleotide variant
Location: chr20:62406968 (GRCh38)
Gene constraint: LOEUF 1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.39
Residue 103: the 'disordered' region

Full CABLES2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CABLES2 p.Arg128His Uncertain significance ★★ ⚠ same type
CABLES2 p.Ala13Asp Uncertain significance ★ ⚠ same type
CABLES2 p.Ala17Thr Uncertain significance ★ ⚠ same type
CABLES2 p.Ala23Asp Uncertain significance ★ ⚠ same type
CABLES2 p.Ala23Thr Uncertain significance ★ ⚠ same type
CABLES2 p.Ala287Val Uncertain significance ★ ⚠ same type
CABLES2 p.Ala35Val Uncertain significance ★ ⚠ same type
CABLES2 p.Ala384Val 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/cables2-p-leu103 (accessed [today's date]).

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