Is COL4A4 p.Ser318Phe (c.953C>T) pathogenic?

COL4A4 p.Ser318Phe (c.953C>T) is classified Uncertain significance in COL4A4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-26). AlphaMissense: likely benign (0.0923); Ultra-rare (popmax 0.0333%, mid); Associated with Inborn genetic diseases.

What condition is associated with COL4A4 p.Ser318Phe (c.953C>T)?

COL4A4 p.Ser318Phe (c.953C>T) is associated with Inborn genetic diseases (ClinVar).

How common is COL4A4 p.Ser318Phe (c.953C>T) in the general population?

COL4A4 p.Ser318Phe (c.953C>T) is ultra-rare (popmax 0.0333%, mid) (gnomAD).

What do computational predictors say about COL4A4 p.Ser318Phe (c.953C>T)?

AlphaMissense predicts likely benign (score 0.0923) — an in-silico prediction, not a clinical call.

COL4A4 p.Ser318Phe

c.953C>T · rs1187623318 · VCV3063868

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0923 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0923	likely benign
REVEL	0.262	benign-leaning
SaProt	LLR -6.69	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 -0.065, phastCons 0.19
Regional constraint	o/e 0.91	unconstrained · MANE · 140 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	16.88	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0333% Middle Eastern · 2/6,010 alleles

Filtering AF 0.00586% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.000346% 5/1,444,232 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0333%	3,005
Admixed American	0.00339%	29,522
Remaining individualsnot grpmax-eligible	0.00162%	61,742

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: COL4A4
Protein: p.Ser318Phe
Coding: c.953C>T
MANE Select: NM_000092
dbSNP: rs1187623318
Type: single nucleotide variant
Location: chr2:227101887 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 318: the 'triple-helical region' region

Full COL4A4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COL4A4 p.Ser318= Likely benign ★ same residue
COL4A4 p.Arg349Ter Pathogenic/Likely pathogenic ★★ same condition
COL4A4 p.Cys1588Ser Likely pathogenic ★★ same condition
COL4A4 c.4522+6G>A Uncertain significance ★★ same condition
COL4A4 p.Ala1546Thr Uncertain significance ★★ ⚠ same condition
COL4A4 p.Arg1565Cys Uncertain significance ★★ ⚠ same condition
COL4A4 p.Arg641Gln Uncertain significance ★★ ⚠ same condition
COL4A4 p.Arg811Thr Uncertain significance ★★ ⚠ 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/col4a4-p-ser318phe (accessed [today's date]).

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