Is TIMCC p.Arg185His (c.554G>A) pathogenic?

TIMCC p.Arg185His (c.554G>A) is classified Benign in TIMCC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-01). AlphaMissense: ambiguous (0.4616); Rare (popmax 0.15%, sas).

How common is TIMCC p.Arg185His (c.554G>A) in the general population?

TIMCC p.Arg185His (c.554G>A) is rare (popmax 0.15%, sas) (gnomAD).

What do computational predictors say about TIMCC p.Arg185His (c.554G>A)?

AlphaMissense predicts ambiguous (score 0.4616) — an in-silico prediction, not a clinical call.

TIMCC p.Arg185His

c.554G>A · rs543076072 · VCV1879473

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4616 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.15%, sas)

Computational evidence

Protein change
AlphaMissense	0.4616	ambiguous
REVEL	0.405	indeterminate
SaProt	LLR -13.05	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 0.045, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 4,719 bp · p 0.74 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R78H vs ClinVar R185H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.15% South Asian · 137/91,066 alleles

Filtering AF 0.13% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.122%

Overall 0.0107% 173/1,613,590 alleles · rare exomes 159/1,461,356 · genomes 14/152,234 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.15%	665
Remaining individualsnot grpmax-eligible	0.024%	4,165
Middle Eastern	0.0165%	6,060
East Asian	0.00892%	11,213
European (non-Finnish)	0.00136%	73,731

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.Arg185His
Coding: c.554G>A
MANE Select: NM_001329752
dbSNP: rs543076072
Type: single nucleotide variant
Location: chr2:70297473 (GRCh38)
Structure: AlphaFold pLDDT 95.42
Residue 78 UniProt numbering: a UniProt-annotated variant site (found in patients with meniere disease; uncertain significance; reduced mrna expression; mislocalization to the cytosol)

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

Similar variants

TIMCC p.Arg185Cys Likely benign ★ 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-arg185his (accessed [today's date]).

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