Is TIMCC p.Arg141Gln (c.422G>A) pathogenic?

TIMCC p.Arg141Gln (c.422G>A) is classified Uncertain significance in TIMCC (ClinVar, Single submitter, 2 submitters; last evaluated 2024-03-20). AlphaMissense: likely benign (0.0788); Ultra-rare (popmax 0.0268%, eas).

How common is TIMCC p.Arg141Gln (c.422G>A) in the general population?

TIMCC p.Arg141Gln (c.422G>A) is ultra-rare (popmax 0.0268%, eas) (gnomAD).

What do computational predictors say about TIMCC p.Arg141Gln (c.422G>A)?

AlphaMissense predicts likely benign (score 0.0788) — an in-silico prediction, not a clinical call.

TIMCC p.Arg141Gln

c.422G>A · VCV3277174

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0788 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0268%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0788	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -9.54	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.5	GERP -0.2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 4,719 bp · p 0.74 · regional, not allelic
Overall
CADD	21.5	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R34Q vs ClinVar R141Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0268% East Asian · 12/44,760 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00714% 115/1,611,486 alleles · ultra-rare exomes 105/1,459,352 · genomes 10/152,134 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0268%	3,730
Middle Eastern	0.0165%	6,062
South Asian	0.0143%	7,001
European (non-Finnish)	0.00705%	14,193
Remaining individualsnot grpmax-eligible	0.00321%	31,180
Finnishnot grpmax-eligible	0.00312%	32,002
African / African-American	0.00267%	37,427

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.Arg141Gln
Coding: c.422G>A
MANE Select: NM_001329752
Type: single nucleotide variant
Location: chr2:70300967 (GRCh38)
Structure: AlphaFold pLDDT 95.42

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

Similar variants

TIMCC p.Asn24= Benign/Likely benign ★★ same type
FAM136A p.Gln183Ter Pathogenic ★ same type
FAM136A p.Ala12Val Uncertain significance ★ ⚠ same type
FAM136A p.Ala144Thr Uncertain significance ★ same type
FAM136A p.Ala203Asp Uncertain significance ★ ⚠ same type
FAM136A p.Ala2Val Uncertain significance ★ ⚠ same type
FAM136A p.Arg163Gly Uncertain significance ★ ⚠ same type
FAM136A p.Gln10His Uncertain significance ★ ⚠ 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-arg141gln (accessed [today's date]).

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