Is COL4A6 p.Phe456= (c.1368C>T) pathogenic?

COL4A6 p.Phe456= (c.1368C>T) is classified Likely benign in COL4A6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-12-27). Ultra-rare (popmax 0.016%, sas).

How common is COL4A6 p.Phe456= (c.1368C>T) in the general population?

COL4A6 p.Phe456= (c.1368C>T) is ultra-rare (popmax 0.016%, sas) (gnomAD).

COL4A6 p.Phe456=

c.1368C>T · rs770706189 · VCV1318345

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.17	GERP -2.2, phastCons 0.009
Overall
CADD	4.738	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.016% South Asian · 9/56,200 alleles

Filtering AF 0.00831% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00623%

Overall 0.00357% 43/1,204,498 alleles · ultra-rare exomes 41/1,093,359 · genomes 2/111,139 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.016%	6,244
Remaining individualsnot grpmax-eligible	0.00844%	11,854
Admixed American	0.0044%	22,750
European (non-Finnish)	0.00314%	31,840

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: COL4A6
Protein: p.Phe456=
Coding: c.1368C>T
MANE Select: NM_033641
dbSNP: rs770706189
Type: single nucleotide variant
Location: chrX:108190450 (GRCh38)
Structure: AlphaFold pLDDT 48.27
Residue 456: the 'triple-helical region' region; the 'disordered' region

Full COL4A6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COL4A6 p.Phe456Ile Uncertain significance ★ ⚠ same residue
COL4A6 c.3970+5G>A Uncertain significance ★★ same type
COL4A6 p.Ala1275Thr Uncertain significance ★★ ⚠ same type
COL4A6 p.Ala398Ser Uncertain significance ★★ ⚠ same type
COL4A6 p.Ala421Gly Uncertain significance ★★ ⚠ same type
COL4A6 p.Ala748Val Uncertain significance ★★ ⚠ same type
COL4A6 p.Ala886Thr Uncertain significance ★★ ⚠ same type
COL4A6 p.Arg1025Trp 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/col4a6-p-phe456 (accessed [today's date]).

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