Is COL18A1 p.Pro1104Arg (c.3311C>G) pathogenic?

COL18A1 p.Pro1104Arg (c.3311C>G) is classified Benign/Likely benign in COL18A1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.12); Low-frequency (popmax 1.6%, nfe).

How common is COL18A1 p.Pro1104Arg (c.3311C>G) in the general population?

COL18A1 p.Pro1104Arg (c.3311C>G) is low-frequency (popmax 1.6%, nfe) (gnomAD).

What do computational predictors say about COL18A1 p.Pro1104Arg (c.3311C>G)?

AlphaMissense predicts likely benign (score 0.12) — an in-silico prediction, not a clinical call.

COL18A1 p.Pro1104Arg

c.3311C>G · rs187670025 · VCV1169110

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.12 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.6%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.12	likely benign
REVEL	0.116	moderately benign-leaning
SaProt	LLR -7.10	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 2.1	GERP 1.2, phastCons 0.006
Regional constraint	o/e 1.10	unconstrained · MANE · 107 kb · p 4.9e-06 · regional, not allelic
Overall
CADD	20.4	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 P1519R vs ClinVar P1104R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.6% European (non-Finnish) · 18,293/1,143,496 alleles

Filtering AF 1.58% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.57%

Overall 1.39% 21,368/1,539,094 alleles · low-frequency exomes 19,748/1,386,868 · genomes 1,620/152,226 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.6%	63
Remaining individualsnot grpmax-eligible	1.29%	77
Finnishnot grpmax-eligible	1.27%	79
Ashkenazi Jewishnot grpmax-eligible	1.24%	81
Middle Eastern	1.19%	84
Admixed American	0.813%	123
South Asian	0.779%	128
Amishnot grpmax-eligible	0.768%	130
African / African-American	0.204%	490

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.Pro1104Arg
Coding: c.3311C>G
MANE Select: NM_001379500
dbSNP: rs187670025
Type: single nucleotide variant
Location: chr21:45509417 (GRCh38)
Gene constraint: LOEUF 1.001 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 51.77 · 9 PDB
Residue 1519 UniProt numbering: the 'nonhelical region 11 (nc11)' region; the 'non-collagenous domain 1 hinge region' region; the 'disordered' region

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

Similar variants

COL18A1 p.Pro1104= Likely benign ★★ same residue
COL18A1 p.Pro1104Gln Uncertain significance ★ ⚠ same residue
COL18A1 p.Pro1104Leu Uncertain significance ★ ⚠ same residue
COL18A1 p.Pro1104Ser Uncertain significance ★ ⚠ same residue
COL18A1 p.Pro1104Trp Uncertain significance ★ 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

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-pro1104arg (accessed [today's date]).

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