Is TIMCC p.Cys217fs (c.650_651insGCTG) pathogenic?

TIMCC p.Cys217fs (c.650651insGCTG) is classified Likely benign in TIMCC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-26). Low-frequency (popmax 2.79%, amr).

How common is TIMCC p.Cys217fs (c.650_651insGCTG) in the general population?

TIMCC p.Cys217fs (c.650_651insGCTG) is low-frequency (popmax 2.79%, amr) (gnomAD).

TIMCC p.Cys217fs

c.650_651insGCTG · VCV4955460

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

low-frequency (popmax 2.79%, 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 1.5	GERP -1.6, phastCons 1
Overall
CADD	34.0	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 2.79% Admixed American · 1,235/44,312 alleles

Filtering AF 2.66% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.61%

Overall 1.48% 20,014/1,352,708 alleles · low-frequency exomes 15,230/1,238,076 · genomes 4,784/114,632 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	10.6%	9
Admixed Americangrpmax	2.79%	36
East Asian	2.03%	49
European (non-Finnish)	1.48%	67
African / African-American	1.39%	72
Ashkenazi Jewishnot grpmax-eligible	1.25%	80
Remaining individualsnot grpmax-eligible	1.23%	81
South Asian	1.09%	92
Finnishnot grpmax-eligible	1%	100
Middle Eastern	0.489%	204

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.Cys217fs
Coding: c.650_651insGCTG
MANE Select: NM_001329752
Type: Insertion
Location: chr2:70297376 (GRCh38)
Structure: AlphaFold pLDDT 95.42

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

Similar variants

TIMCC c.550-4_550-3insGCTGTCGTGAGGACAGGCAGGCTTCCATGCAGCAGGTGCACCAGTGTGTCAAACTCTGCCATGTTCCTCTGGCTTAATCCCAGGCTTTGGTCACCAGTGAGTTC Likely benign ★ same type
TIMCC c.550-4_550-3insGGCTTCCATGCAGCAGGTGCACCAGTGTGTCAAACTCTGCCATGTTCCTCTGGCTTAATCCCAGGCTTTGGTCACCAGTGAGTTC Likely 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/timcc-p-cys217fs (accessed [today's date]).

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