Is TIMCC p.Asp215fs (c.644_647del) pathogenic?

TIMCC p.Asp215fs (c.644647del) is classified Likely benign in TIMCC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-26). Low-frequency (popmax 3.08%, amr).

How common is TIMCC p.Asp215fs (c.644_647del) in the general population?

TIMCC p.Asp215fs (c.644_647del) is low-frequency (popmax 3.08%, amr) (gnomAD).

TIMCC p.Asp215fs

c.644_647del · rs761817680 · VCV2651013

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

low-frequency (popmax 3.08%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.4	GERP -2.3, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.08% Admixed American · 1,231/40,022 alleles

Filtering AF 2.93% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.88%

Overall 2.11% 23,651/1,121,860 alleles · low-frequency exomes 19,218/1,012,300 · genomes 4,433/109,560 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	10.7%	9
Admixed Americangrpmax	3.08%	33
European (non-Finnish)	2.3%	44
East Asian	2.19%	46
Remaining individualsnot grpmax-eligible	1.75%	57
Ashkenazi Jewishnot grpmax-eligible	1.46%	68
African / African-American	1.41%	71
South Asian	1.22%	82
Finnishnot grpmax-eligible	1.04%	96
Middle Eastern	0.686%	146

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: TIMCC
Protein: p.Asp215fs
Coding: c.644_647del
MANE Select: NM_001329752
dbSNP: rs761817680
Type: Deletion
Location: chr2:70297380 (GRCh38)
Structure: AlphaFold pLDDT 95.42

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

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/timcc-p-asp215fs (accessed [today's date]).

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