Is COMP p.Phe137Ser (c.410T>C) pathogenic?

COMP p.Phe137Ser (c.410T>C) is classified Benign/Likely benign in COMP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-02). AlphaMissense: likely pathogenic (0.6326); Ultra-rare (popmax 0.0257%, nfe); Associated with connective tissue disorder.

What condition is associated with COMP p.Phe137Ser (c.410T>C)?

COMP p.Phe137Ser (c.410T>C) is associated with connective tissue disorder, multiple epiphyseal dysplasia type 1, pseudoachondroplasia (ClinVar).

How common is COMP p.Phe137Ser (c.410T>C) in the general population?

COMP p.Phe137Ser (c.410T>C) is ultra-rare (popmax 0.0257%, nfe) (gnomAD).

What do computational predictors say about COMP p.Phe137Ser (c.410T>C)?

AlphaMissense predicts likely pathogenic (score 0.6326) — an in-silico prediction, not a clinical call.

COMP p.Phe137Ser

c.410T>C · rs757094319 · VCV328623

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6326 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0257%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

connective tissue disorder

Computational evidence

Protein change
AlphaMissense	0.6326	likely pathogenic
REVEL	0.128	moderately benign-leaning
SaProt	LLR -9.12	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	27.8	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 0.0257% European (non-Finnish) · 290/1,128,244 alleles

Filtering AF 0.0232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0223%

Overall 0.0203% 304/1,500,312 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0257%	3,890
Remaining individualsnot grpmax-eligible	0.0191%	5,225
Admixed American	0.00731%	13,678

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.Phe137Ser
Coding: c.410T>C
MANE Select: NM_000095
dbSNP: rs757094319
Type: single nucleotide variant
Location: chr19:18789278 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 137: the egf-like 2; calcium-binding domain; a disulfide bond

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

Disease context

connective tissue disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: multiple epiphyseal dysplasia type 1 pseudoachondroplasia

Similar variants

COMP p.Phe137= Likely benign ★ same residue
COMP p.Arg718Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
COMP p.Asn489Lys Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asn523Lys Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asn555Lys Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asp269Gly Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asp273Val Likely pathogenic ★★ same condition
COMP p.Asp326Asn Pathogenic/Likely pathogenic ★★ 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-phe137ser (accessed [today's date]).

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