TRAPPC12 p.Phe227=

Q: Is TRAPPC12 p.Phe227= (c.681T>C) pathogenic?

TRAPPC12 p.Phe227= (c.681T>C) is classified Benign in TRAPPC12 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). Common (popmax 70.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome.

Q: What condition is associated with TRAPPC12 p.Phe227= (c.681T>C)?

TRAPPC12 p.Phe227= (c.681T>C) is associated with early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome (ClinVar).

Q: How common is TRAPPC12 p.Phe227= (c.681T>C) in the general population?

TRAPPC12 p.Phe227= (c.681T>C) is common (popmax 70.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.681T>C · rs10865541 · VCV1282559

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 70.3%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.063	GERP -0.65, phastCons 0.92
Overall
CADD	6.501	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 70.3% African / African-American · 51,835/73,692 alleles

Filtering AF 69.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 69.6%

Overall 59.3% 953,228/1,606,390 alleles · common exomes 858,899/1,454,478 · genomes 94,329/151,912 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	78%	1
African / African-Americangrpmax	70.3%	1
East Asian	68%	1
Middle Eastern	66.6%	2
South Asian	65.1%	2
Ashkenazi Jewishnot grpmax-eligible	63%	2
Finnishnot grpmax-eligible	61.3%	2
Remaining individualsnot grpmax-eligible	60.9%	2
European (non-Finnish)	58.1%	2
Admixed American	48.5%	2

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe227=
Coding: c.681T>C
MANE Select: NM_016030
dbSNP: rs10865541
Type: single nucleotide variant
Location: chr2:3388304 (GRCh38)
Gene constraint: LOEUF 1.192 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.52

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.Phe227Leu Uncertain significance ★★ ⚠ same residue
TRAPPC12 p.Phe227Cys Uncertain significance ★ ⚠ same residue
TRAPPC12 p.Phe227Ser Uncertain significance ★ ⚠ same residue
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.Arg166Ser Uncertain significance ★★ ⚠ same condition
TRAPPC12 p.Arg533Gly 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-phe227 (accessed [today's date]).

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