Is TRAPPC9 p.Ala421Val (c.1262C>T) pathogenic?

TRAPPC9 p.Ala421Val (c.1262C>T) is classified Uncertain significance in TRAPPC9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-23). AlphaMissense: likely benign (0.0729); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with TRAPPC9 p.Ala421Val (c.1262C>T)?

TRAPPC9 p.Ala421Val (c.1262C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TRAPPC9 p.Ala421Val (c.1262C>T) in the general population?

TRAPPC9 p.Ala421Val (c.1262C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about TRAPPC9 p.Ala421Val (c.1262C>T)?

AlphaMissense predicts likely benign (score 0.0729) — an in-silico prediction, not a clinical call.

TRAPPC9 p.Ala421Val

c.1262C>T · rs377644857 · VCV1775157

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0729 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0729	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -6.76	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 3.9	GERP 0.98, phastCons 0.79
Regional constraint	o/e 0.81	unconstrained · MANE · 160 kb · p 6.1e-08 · regional, not allelic
Overall
CADD	21.1	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00266% 43/1,614,128 alleles · ultra-rare exomes 37/1,461,876 · genomes 6/152,252 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0048%	20,829
African / African-American	0.004%	24,986
European (non-Finnish)	0.00288%	34,707
South Asian	0.0022%	45,546

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: TRAPPC9
Protein: p.Ala421Val
Coding: c.1262C>T
MANE Select: NM_001160372
dbSNP: rs377644857
Type: single nucleotide variant
Location: chr8:140371053 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.98

Full TRAPPC9 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

TRAPPC9 p.Ala421= Likely benign ★★ same residue
TRAPPC9 p.Arg472Ter Pathogenic/Likely pathogenic ★★ same condition
TRAPPC9 p.Glu123Ter Pathogenic ★★ same condition
TRAPPC9 p.Glu97Ter Pathogenic ★★ same condition
TRAPPC9 c.-212G>C Uncertain significance ★★ same condition
TRAPPC9 c.-4C>A Uncertain significance ★★ same condition
TRAPPC9 c.-69C>T Uncertain significance ★★ same condition
TRAPPC9 c.-74C>A 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/trappc9-p-ala421val (accessed [today's date]).

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