Is TRAPPC4 p.Ala65Val (c.194C>T) pathogenic?

TRAPPC4 p.Ala65Val (c.194C>T) is classified Uncertain significance in TRAPPC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-07). AlphaMissense: likely pathogenic (0.6114); Very rare (popmax 0.00133%, afr).

How common is TRAPPC4 p.Ala65Val (c.194C>T) in the general population?

TRAPPC4 p.Ala65Val (c.194C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about TRAPPC4 p.Ala65Val (c.194C>T)?

AlphaMissense predicts likely pathogenic (score 0.6114) — an in-silico prediction, not a clinical call.

TRAPPC4 p.Ala65Val

c.194C>T · rs558283221 · VCV2534882

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6114 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6114	likely pathogenic
REVEL	0.33	indeterminate
SaProt	LLR -13.17	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 1.6, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 3,028 bp · p 0.78 · regional, not allelic
Overall
CADD	26.4	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 0.00133% African / African-American · 1/75,048 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,614,136 alleles · very rare exomes 3/1,461,822 · genomes 0/152,314 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,048
European (non-Finnish)	0.000169%	589,991

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.Ala65Val
Coding: c.194C>T
MANE Select: NM_016146
dbSNP: rs558283221
Type: single nucleotide variant
Location: chr11:119019161 (GRCh38)
Gene constraint: LOEUF 1.689 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.02 · 3 PDB
Residue 65: a β-strand

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

Similar variants

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
TRAPPC4 c.454+225G>T 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-ala65val (accessed [today's date]).

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