Is COL4A6 p.Ser454Pro (c.1360T>C) pathogenic?

COL4A6 p.Ser454Pro (c.1360T>C) is classified Benign in COL4A6 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0452); Common (popmax 79%, mid) — too common for a highly-penetrant pathogenic allele; Associated with hearing loss, X-linked 6.

What condition is associated with COL4A6 p.Ser454Pro (c.1360T>C)?

COL4A6 p.Ser454Pro (c.1360T>C) is associated with hearing loss, X-linked 6 (ClinVar).

What do computational predictors say about COL4A6 p.Ser454Pro (c.1360T>C)?

AlphaMissense predicts likely benign (score 0.0452) — an in-silico prediction, not a clinical call.

COL4A6 p.Ser454Pro

Q: How common is COL4A6 p.Ser454Pro (c.1360T>C) in the general population?

COL4A6 p.Ser454Pro (c.1360T>C) is common (popmax 79%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1360T>C · rs1042065 · VCV258267

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0452 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 79%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hearing loss, X-linked 6

Computational evidence

Protein change
AlphaMissense	0.0452	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -4.84	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 -1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 281 kb · p 0.15 · regional, not allelic
Overall
CADD	2.924	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 S455P vs ClinVar S454P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 79% Middle Eastern · 3,415/4,321 alleles

Filtering AF 78.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 78.4%

Overall 74.6% 897,641/1,203,066 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	85.5%	1
Ashkenazi Jewishnot grpmax-eligible	81.2%	1
Middle Easterngrpmax	79%	1
European (non-Finnish)	78.6%	1
Amishnot grpmax-eligible	77.9%	1
Remaining individualsnot grpmax-eligible	73.4%	1
African / African-American	64.1%	2
South Asian	61.9%	2
Admixed American	41.9%	2
East Asian	33.5%	3

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser454Pro
Coding: c.1360T>C
MANE Select: NM_033641
dbSNP: rs1042065
Type: single nucleotide variant
Location: chrX:108190458 (GRCh38)
Structure: AlphaFold pLDDT 48.27
Residue 454: the 'triple-helical region' region; the 'disordered' region

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

Disease context

hearing loss, X-linked 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COL4A6 p.Arg1269Ter Uncertain significance ★★ same condition
COL4A6 p.Gly1484Arg Uncertain significance ★★ ⚠ same condition
COL4A6 c.2132-6G>A Benign/Likely benign ★★ same condition
COL4A6 c.2132-6G>T Benign/Likely benign ★★ same condition
COL4A6 c.2956+39G>A Benign ★★ same condition
COL4A6 c.3138+17C>T Benign/Likely benign ★★ same condition
COL4A6 c.3139-4G>A Benign/Likely benign ★★ same condition
COL4A6 c.3809-14G>A Benign/Likely benign ★★ same condition

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-ser454pro (accessed [today's date]).

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