Is COL18A1 p.Pro705Ser (c.2113C>T) pathogenic?

COL18A1 p.Pro705Ser (c.2113C>T) is classified Uncertain significance in COL18A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-21). AlphaMissense: likely benign (0.1993); Very rare (popmax 0.0022%, sas).

How common is COL18A1 p.Pro705Ser (c.2113C>T) in the general population?

COL18A1 p.Pro705Ser (c.2113C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about COL18A1 p.Pro705Ser (c.2113C>T)?

AlphaMissense predicts likely benign (score 0.1993) — an in-silico prediction, not a clinical call.

COL18A1 p.Pro705Ser

c.2113C>T · rs765760874 · VCV1366503

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1993 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1993	likely benign
REVEL	0.537	indeterminate
SaProt	LLR -11.39	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 7.3	GERP 1.4, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 107 kb · p 4.9e-06 · regional, not allelic
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1120S vs ClinVar P705S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,008 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000248% 4/1,612,222 alleles · very rare exomes 4/1,459,964 · genomes 0/152,258 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,504
European (non-Finnish)	0.00017%	589,845

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: COL18A1
Protein: p.Pro705Ser
Coding: c.2113C>T
MANE Select: NM_001379500
dbSNP: rs765760874
Type: single nucleotide variant
Location: chr21:45491270 (GRCh38)
Gene constraint: LOEUF 1.001 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 51.77 · 9 PDB
Residue 1120 UniProt numbering: the 'triple-helical region 4 (col4)' region; the 'disordered' region

Full COL18A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COL18A1 p.Pro705Leu Uncertain significance ★★ ⚠ same residue
COL18A1 p.Pro705Thr Uncertain significance ★★ ⚠ same residue
COL18A1 p.Pro705Ala Uncertain significance ★ ⚠ same residue
COL18A1 p.Pro705= Likely benign ★ same residue
COL18A1 c.1897-2A>G Likely pathogenic ★★ same type
COL18A1 c.2157+1G>A Likely pathogenic ★★ same type
COL18A1 c.2577+1G>A Pathogenic/Likely pathogenic ★★ same type
COL18A1 c.3013+3A>C 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/col18a1-p-pro705ser (accessed [today's date]).

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