Is COMP c.165+41G>C pathogenic?

COMP c.165+41G>C is classified Benign in COMP (ClinVar, Multiple submitters, 2 submitters). Common (popmax 29.7%, afr) — too common for a highly-penetrant pathogenic allele.

COMP c.165+41G>C

Q: How common is COMP c.165+41G>C in the general population?

COMP c.165+41G>C is common (popmax 29.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs35359254 · VCV255118

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 29.7%, afr) — 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
Splice region	donor +41	near-intronic (+41 nt from the splice site)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.077	GERP -1.2
Non-coding constraint	Z 3.45	1 kb window · o/e 0.73 · regional · uncalibrated
Overall
CADD	4.704	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 29.7% African / African-American · 21,850/73,598 alleles

Filtering AF 29.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 29.2%

Overall 10.1% 156,923/1,558,104 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	29.7%	3
Finnishnot grpmax-eligible	13.4%	7
European (non-Finnish)	9.85%	10
Remaining individualsnot grpmax-eligible	9.42%	11
Amishnot grpmax-eligible	8.99%	11
Ashkenazi Jewishnot grpmax-eligible	8.35%	12
Middle Eastern	6.68%	15
Admixed American	6.17%	16
South Asian	2.46%	41
East Asian	0.827%	121

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: COMP
Coding: c.165+41G>C
MANE Select: NM_000095
dbSNP: rs35359254
Type: single nucleotide variant
Location: chr19:18790809 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB

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

Similar variants

COMP p.Arg718Trp Pathogenic/Likely pathogenic ★★ same type
COMP p.Asn489Lys Pathogenic/Likely pathogenic ★★ same type
COMP p.Asn523Lys Pathogenic/Likely pathogenic ★★ ⚠ same type
COMP p.Asn555Lys Pathogenic/Likely pathogenic ★★ same type
COMP p.Asp269Gly Pathogenic/Likely pathogenic ★★ same type
COMP p.Asp273Val Likely pathogenic ★★ same type
COMP p.Asp326Asn Pathogenic/Likely pathogenic ★★ same type
COMP p.Asp349His Pathogenic ★★ 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/comp-c-165-plus-41g-c (accessed [today's date]).

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