Is GTF2E2 p.Ser48Pro (c.142T>C) pathogenic?

GTF2E2 p.Ser48Pro (c.142T>C) is classified Uncertain significance in GTF2E2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-06). AlphaMissense: likely benign (0.0811); Ultra-rare (popmax 0.0217%, amr).

How common is GTF2E2 p.Ser48Pro (c.142T>C) in the general population?

GTF2E2 p.Ser48Pro (c.142T>C) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about GTF2E2 p.Ser48Pro (c.142T>C)?

AlphaMissense predicts likely benign (score 0.0811) — an in-silico prediction, not a clinical call.

GTF2E2 p.Ser48Pro

c.142T>C · rs771803770 · VCV1366190

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0811 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0811	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -7.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 75 kb · p 0.028 · regional, not allelic
Overall
CADD	20.9	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 0.0217% Admixed American · 13/59,896 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.00143% 23/1,613,470 alleles · ultra-rare exomes 14/1,461,308 · genomes 9/152,162 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,607
African / African-American	0.00534%	18,720
European (non-Finnish)	0.000509%	196,632

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: GTF2E2
Protein: p.Ser48Pro
Coding: c.142T>C
MANE Select: NM_002095
dbSNP: rs771803770
Type: single nucleotide variant
Location: chr8:30653457 (GRCh38)
Gene constraint: LOEUF 1.107 · pLI 0.40 (gnomAD)
Structure: AlphaFold pLDDT 68.97 · 46 PDB
Residue 48: the 'disordered' region

Full GTF2E2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GTF2E2 p.Ser48= Benign/Likely benign ★★ same residue
GTF2E2 p.Ser48Leu Uncertain significance ★ ⚠ same residue
GTF2E2 p.Ala138Thr Uncertain significance ★★ ⚠ same type
GTF2E2 p.Ala278Ser Uncertain significance ★★ ⚠ same type
GTF2E2 p.Arg25Cys Uncertain significance ★★ ⚠ same type
GTF2E2 p.Arg269Cys Uncertain significance ★★ ⚠ same type
GTF2E2 p.Gly47Ala Uncertain significance ★★ ⚠ same type
GTF2E2 p.His158Arg 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/gtf2e2-p-ser48pro (accessed [today's date]).

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