Is GTF3C4 p.Pro153Ser (c.457C>T) pathogenic?

GTF3C4 p.Pro153Ser (c.457C>T) is classified Uncertain significance in GTF3C4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-25). AlphaMissense: ambiguous (0.4997); Ultra-rare (popmax 0.0117%, amr).

How common is GTF3C4 p.Pro153Ser (c.457C>T) in the general population?

GTF3C4 p.Pro153Ser (c.457C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about GTF3C4 p.Pro153Ser (c.457C>T)?

AlphaMissense predicts ambiguous (score 0.4997) — an in-silico prediction, not a clinical call.

GTF3C4 p.Pro153Ser

c.457C>T · rs965874077 · VCV2529857

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4997 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Computational evidence

Protein change
AlphaMissense	0.4997	ambiguous
REVEL	0.343	indeterminate
SaProt	LLR -3.81	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 1,349 bp · p 1e-10 · regional, not allelic
Overall
CADD	25.7	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 0.0117% Admixed American · 7/60,002 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000434% 7/1,614,042 alleles · ultra-rare exomes 6/1,461,836 · genomes 1/152,206 · joint denominator

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: GTF3C4
Protein: p.Pro153Ser
Coding: c.457C>T
MANE Select: NM_012204
dbSNP: rs965874077
Type: single nucleotide variant
Location: chr9:132678076 (GRCh38)
Gene constraint: LOEUF 0.502 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 82.73 · 3 PDB

Full GTF3C4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GTF3C4 p.Ala349Val Uncertain significance ★ ⚠ same type
GTF3C4 p.Ala40Thr Uncertain significance ★ ⚠ same type
GTF3C4 p.Ala560Thr Uncertain significance ★ ⚠ same type
GTF3C4 p.Ala7Val Uncertain significance ★ ⚠ same type
GTF3C4 p.Arg190Cys Uncertain significance ★ ⚠ same type
GTF3C4 p.Arg326Gly Uncertain significance ★ ⚠ same type
GTF3C4 p.Arg48His Uncertain significance ★ ⚠ same type
GTF3C4 p.Arg53Trp 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/gtf3c4-p-pro153ser (accessed [today's date]).

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