Is TIMCC p.His227= (c.681C>T) pathogenic?

TIMCC p.His227= (c.681C>T) is classified Likely benign in TIMCC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-26). Low-frequency (popmax 2.67%, amr).

How common is TIMCC p.His227= (c.681C>T) in the general population?

TIMCC p.His227= (c.681C>T) is low-frequency (popmax 2.67%, amr) (gnomAD).

TIMCC p.His227=

c.681C>T · VCV4955459

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

low-frequency (popmax 2.67%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP -0.051, phastCons 1
Overall
CADD	7.743	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.67% Admixed American · 1,133/42,508 alleles

Filtering AF 2.54% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.48%

Overall 0.654% 8,824/1,350,188 alleles · low-frequency exomes 4,465/1,237,352 · genomes 4,359/112,836 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	9.86%	10
Admixed Americangrpmax	2.67%	38
East Asian	1.33%	75
African / African-American	1.23%	82
Ashkenazi Jewishnot grpmax-eligible	0.949%	105
Finnishnot grpmax-eligible	0.812%	123
South Asian	0.812%	123
Remaining individualsnot grpmax-eligible	0.544%	184
European (non-Finnish)	0.483%	207
Middle Eastern	0.248%	404

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.His227=
Coding: c.681C>T
MANE Select: NM_001329752
Type: single nucleotide variant
Location: chr2:70297346 (GRCh38)
Structure: AlphaFold pLDDT 95.42

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

Similar variants

TIMCC p.His227Asp Uncertain significance ★ ⚠ same residue
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

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-his227 (accessed [today's date]).

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