Is COL20A1 p.Pro581Ser (c.1741C>T) pathogenic?

COL20A1 p.Pro581Ser (c.1741C>T) is classified Uncertain significance in COL20A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely benign (0.0675); Ultra-rare (popmax 0.0379%, mid).

How common is COL20A1 p.Pro581Ser (c.1741C>T) in the general population?

COL20A1 p.Pro581Ser (c.1741C>T) is ultra-rare (popmax 0.0379%, mid) (gnomAD).

What do computational predictors say about COL20A1 p.Pro581Ser (c.1741C>T)?

AlphaMissense predicts likely benign (score 0.0675) — an in-silico prediction, not a clinical call.

COL20A1 p.Pro581Ser

c.1741C>T · VCV4655498

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0675 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0379%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0675	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -7.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.72	GERP 0.92
Regional constraint	o/e 1.07	unconstrained · MANE · 35 kb · p 0.0022 · regional, not allelic
Overall
CADD	0.195	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0379% Middle Eastern · 2/5,274 alleles

Filtering AF 0.00672% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00272%

Overall 0.00137% 22/1,605,618 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0379%	2,637
African / African-American	0.00668%	14,972
European (non-Finnish)	0.00127%	78,477

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: COL20A1
Protein: p.Pro581Ser
Coding: c.1741C>T
MANE Select: NM_020882
Type: single nucleotide variant
Location: chr20:63311993 (GRCh38)
Gene constraint: LOEUF 1.419 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.88 · 4 PDB
Residue 581: the fibronectin type-iii 4 domain

Full COL20A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COL20A1 p.Pro581Leu Uncertain significance ★ ⚠ same residue
COL20A1 p.Thr141= Benign ★★ same type
COL20A1 p.Ala1059Pro Uncertain significance ★ ⚠ same type
COL20A1 p.Ala1063Thr Uncertain significance ★ ⚠ same type
COL20A1 p.Ala1244Ser Uncertain significance ★ ⚠ same type
COL20A1 p.Ala1265Thr Uncertain significance ★ ⚠ same type
COL20A1 p.Ala274Thr Uncertain significance ★ ⚠ same type
COL20A1 p.Ala300Thr 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/col20a1-p-pro581ser (accessed [today's date]).

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