Is TRAPPC12 p.Arg166Ser (c.496C>A) pathogenic?

TRAPPC12 p.Arg166Ser (c.496C>A) is classified Uncertain significance in TRAPPC12 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-07-15). AlphaMissense: likely benign (0.098); Ultra-rare (popmax 0.0544%, afr); Associated with early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome.

How common is TRAPPC12 p.Arg166Ser (c.496C>A) in the general population?

TRAPPC12 p.Arg166Ser (c.496C>A) is ultra-rare (popmax 0.0544%, afr) (gnomAD).

What do computational predictors say about TRAPPC12 p.Arg166Ser (c.496C>A)?

AlphaMissense predicts likely benign (score 0.098) — an in-silico prediction, not a clinical call.

TRAPPC12 p.Arg166Ser

Q: What condition is associated with TRAPPC12 p.Arg166Ser (c.496C>A)?

TRAPPC12 p.Arg166Ser (c.496C>A) is associated with early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome (ClinVar).

c.496C>A · rs758495770 · VCV1029570

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.098 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0544%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome

Computational evidence

Protein change
AlphaMissense	0.098	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -4.96	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 -1	GERP -4.5
Regional constraint	o/e 1.08	unconstrained · MANE · 92 kb · p 0.008 · regional, not allelic
Overall
CADD	0.47	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 0.0544% African / African-American · 40/73,594 alleles

Filtering AF 0.0409% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0363%

Overall 0.00463% 73/1,576,272 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0544%	1,840
Admixed American	0.018%	5,567
Middle Eastern	0.0169%	5,908
Remaining individualsnot grpmax-eligible	0.0147%	6,803
South Asian	0.00114%	87,746
European (non-Finnish)	0.00103%	97,080

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: TRAPPC12
Protein: p.Arg166Ser
Coding: c.496C>A
MANE Select: NM_016030
dbSNP: rs758495770
Type: single nucleotide variant
Location: chr2:3388119 (GRCh38)
Gene constraint: LOEUF 1.192 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.52
Residue 166: the 'disordered' region

Full TRAPPC12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRAPPC12 p.Ala627Val Pathogenic/Likely pathogenic ★★ same condition
TRAPPC12 c.1531-3C>T Uncertain significance ★★ same condition
TRAPPC12 c.1603+5G>C Uncertain significance ★★ same condition
TRAPPC12 p.Arg533Gly Uncertain significance ★★ same condition
TRAPPC12 p.Ile593Ser Uncertain significance ★★ ⚠ same condition
TRAPPC12 p.Leu631Arg Uncertain significance ★★ ⚠ same condition
TRAPPC12 p.Phe227Leu Uncertain significance ★★ ⚠ same condition
TRAPPC12 p.Val565Met 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/trappc12-p-arg166ser (accessed [today's date]).

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