Is COMP p.Cys114Ser (c.341G>C) pathogenic?

COMP p.Cys114Ser (c.341G>C) is classified Uncertain significance in COMP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). AlphaMissense: likely pathogenic (0.9946); Very rare (popmax 0.000255%, nfe); Associated with Inborn genetic diseases.

What condition is associated with COMP p.Cys114Ser (c.341G>C)?

COMP p.Cys114Ser (c.341G>C) is associated with Inborn genetic diseases (ClinVar).

How common is COMP p.Cys114Ser (c.341G>C) in the general population?

COMP p.Cys114Ser (c.341G>C) is very rare (popmax 0.000255%, nfe) (gnomAD).

What do computational predictors say about COMP p.Cys114Ser (c.341G>C)?

AlphaMissense predicts likely pathogenic (score 0.9946) — an in-silico prediction, not a clinical call.

COMP p.Cys114Ser

c.341G>C · rs2512854292 · VCV3147936

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9946 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9946	likely pathogenic · top 5% in COMP
REVEL	0.969	strongly pathogenic-leaning
SaProt	LLR -14.31	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000255% European (non-Finnish) · 3/1,176,584 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000208% 3/1,440,346 alleles · very rare

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
Protein: p.Cys114Ser
Coding: c.341G>C
MANE Select: NM_000095
dbSNP: rs2512854292
Type: single nucleotide variant
Location: chr19:18789991 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 114: the egf-like 1 domain; a disulfide bond

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COMP p.Arg247Ser Uncertain significance ★★ ⚠ same condition
COMP p.Arg352Trp Uncertain significance ★★ ⚠ same condition
COMP p.Arg379Gln Uncertain significance ★★ ⚠ same condition
COMP p.Arg381Leu Uncertain significance ★★ ⚠ same condition
COMP p.Arg665Trp Uncertain significance ★★ ⚠ same condition
COMP p.Arg689Trp Uncertain significance ★★ ⚠ same condition
COMP p.Arg721His Uncertain significance ★★ ⚠ same condition
COMP p.Asp422Gly Uncertain significance ★★ ⚠ same condition

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-p-cys114ser (accessed [today's date]).

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