Is TRAPPC4 p.Pro93Ser (c.277C>T) pathogenic?

TRAPPC4 p.Pro93Ser (c.277C>T) is classified Uncertain significance in TRAPPC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-10). AlphaMissense: likely pathogenic (0.9945); Ultra-rare (popmax 0.0174%, afr).

How common is TRAPPC4 p.Pro93Ser (c.277C>T) in the general population?

TRAPPC4 p.Pro93Ser (c.277C>T) is ultra-rare (popmax 0.0174%, afr) (gnomAD).

What do computational predictors say about TRAPPC4 p.Pro93Ser (c.277C>T)?

AlphaMissense predicts likely pathogenic (score 0.9945) — an in-silico prediction, not a clinical call.

TRAPPC4 p.Pro93Ser

c.277C>T · VCV3973042

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9945 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9945	likely pathogenic
REVEL	0.488	indeterminate
SaProt	LLR -12.46	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 3,028 bp · p 0.78 · regional, not allelic
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0174% African / African-American · 13/74,882 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.000929% 15/1,614,002 alleles · ultra-rare exomes 7/1,461,890 · genomes 8/152,112 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0174%	5,760
East Asian	0.00223%	44,902
Admixed American	0.00167%	59,996

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: TRAPPC4
Protein: p.Pro93Ser
Coding: c.277C>T
MANE Select: NM_016146
Type: single nucleotide variant
Location: chr11:119019244 (GRCh38)
Gene constraint: LOEUF 1.689 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.02 · 3 PDB
Residue 93: a β-strand

Full TRAPPC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRAPPC4 p.Pro93Leu Uncertain significance ★ ⚠ same residue
TRAPPC4 c.454+3A>G Pathogenic/Likely pathogenic ★★ same type
TRAPPC4 c.176-31C>G Benign ★★ same type
TRAPPC4 c.176-40C>G Benign ★★ same type
TRAPPC4 c.176-43C>T Benign ★★ same type
TRAPPC4 c.350+129T>C Benign ★★ same type
TRAPPC4 c.350+58C>T Benign ★★ same type
TRAPPC4 c.351-58C>A Benign ★★ 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/trappc4-p-pro93ser (accessed [today's date]).

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