Is COL4A5 p.Pro668Ser (c.2002C>T) pathogenic?

COL4A5 p.Pro668Ser (c.2002C>T) is classified Uncertain significance in COL4A5 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-23). AlphaMissense: likely benign (0.1083); Very rare (popmax 0.000336%, nfe).

How common is COL4A5 p.Pro668Ser (c.2002C>T) in the general population?

COL4A5 p.Pro668Ser (c.2002C>T) is very rare (popmax 0.000336%, nfe) (gnomAD).

What do computational predictors say about COL4A5 p.Pro668Ser (c.2002C>T)?

AlphaMissense predicts likely benign (score 0.1083) — an in-silico prediction, not a clinical call.

COL4A5 p.Pro668Ser

c.2002C>T · rs2147819433 · VCV1311314

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1083 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000336%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1083	likely benign
REVEL	0.715	pathogenic-leaning
SaProt	LLR -11.33	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 256 kb · p 6e-09 · regional, not allelic
Overall
CADD	23.4	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 0.000336% European (non-Finnish) · 3/893,498 alleles

Filtering AF 8.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000274% 3/1,094,554 alleles · very rare

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: COL4A5
Protein: p.Pro668Ser
Coding: c.2002C>T
MANE Select: NM_033380
dbSNP: rs2147819433
Type: single nucleotide variant
Location: chrX:108601446 (GRCh38)
Structure: AlphaFold pLDDT 49.04 · 2 PDB
Residue 668: the 'triple-helical region' region; the 'disordered' region

Full COL4A5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COL4A5 p.Pro668Leu Uncertain significance ★★ ⚠ same residue
COL4A5 p.Pro668= Likely benign ★ same residue
COL4A5 c.1032+1G>C Pathogenic/Likely pathogenic ★★ same type
COL4A5 c.1033-1G>A Pathogenic ★★ same type
COL4A5 c.1033-2A>G Pathogenic/Likely pathogenic ★★ same type
COL4A5 c.1339+1G>A Pathogenic/Likely pathogenic ★★ same type
COL4A5 c.141+1G>A Pathogenic ★★ same type
COL4A5 c.1423+1G>A 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/col4a5-p-pro668ser (accessed [today's date]).

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