Is COL2A1 p.Pro170Ser (c.508C>T) pathogenic?

COL2A1 p.Pro170Ser (c.508C>T) is classified Conflicting classifications of pathogenicity in COL2A1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-10-22). AlphaMissense: likely benign (0.0637); Very rare (popmax 0.00161%, nfe).

How common is COL2A1 p.Pro170Ser (c.508C>T) in the general population?

COL2A1 p.Pro170Ser (c.508C>T) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about COL2A1 p.Pro170Ser (c.508C>T)?

AlphaMissense predicts likely benign (score 0.0637) — an in-silico prediction, not a clinical call.

COL2A1 p.Pro170Ser

c.508C>T · rs200882049 · VCV451900

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0637 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0637	likely benign
REVEL	0.622	indeterminate
SaProt	LLR -11.13	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 7,716 bp · p 0.0078 · regional, not allelic
Overall
CADD	22.2	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 0.00161% European (non-Finnish) · 19/1,179,894 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.0114% 184/1,613,716 alleles · very rare exomes 142/1,461,592 · genomes 42/152,124 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.252%	397
Remaining individualsnot grpmax-eligible	0.0064%	15,619
European (non-Finnish)grpmax	0.00161%	62,100

Finnish 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: COL2A1
Protein: p.Pro170Ser
Coding: c.508C>T
MANE Select: NM_001844
dbSNP: rs200882049
Type: single nucleotide variant
Location: chr12:47997629 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 170: the 'disordered' region

Full COL2A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COL2A1 p.Pro170Leu Uncertain significance ★ ⚠ same residue
COL2A1 p.Pro170fs Pathogenic ★ same residue
COL2A1 c.1023+1G>A Pathogenic ★★ same type
COL2A1 c.1024-2A>C Pathogenic ★★ same type
COL2A1 c.1069-2A>G Pathogenic/Likely pathogenic ★★ same type
COL2A1 c.1221+1G>A Pathogenic ★★ same type
COL2A1 c.1222-2A>G Pathogenic ★★ same type
COL2A1 c.1365+1G>A Pathogenic/Likely 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/col2a1-p-pro170ser (accessed [today's date]).

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