Is TIMCC p.Asp195His (c.583G>C) pathogenic?

TIMCC p.Asp195His (c.583G>C) is classified Likely benign in TIMCC (ClinVar, Single submitter, 2 submitters; last evaluated 2024-11-26). AlphaMissense: likely pathogenic (0.9834); Common (popmax 9.41%, amr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about TIMCC p.Asp195His (c.583G>C)?

AlphaMissense predicts likely pathogenic (score 0.9834) — an in-silico prediction, not a clinical call.

TIMCC p.Asp195His

Q: How common is TIMCC p.Asp195His (c.583G>C) in the general population?

TIMCC p.Asp195His (c.583G>C) is common (popmax 9.41%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.583G>C · rs75086964 · VCV3055771

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9834 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 9.41%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9834	likely pathogenic · top 7% in TIMCC
REVEL	0.69	pathogenic-leaning
SaProt	LLR -14.73	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 4,719 bp · p 0.74 · regional, not allelic
Overall
CADD	30.0	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 D88H vs ClinVar D195H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.41% Admixed American · 4,367/46,408 alleles

Filtering AF 9.18% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.08%

Overall 6.35% 74,606/1,175,608 alleles · common exomes 71,351/1,047,294 · genomes 3,255/128,314 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	9.41%	11
European (non-Finnish)	7.22%	14
Ashkenazi Jewishnot grpmax-eligible	5.74%	17
Amishnot grpmax-eligible	5.51%	18
Remaining individualsnot grpmax-eligible	5.3%	19
East Asian	4.27%	23
South Asian	3.51%	28
Middle Eastern	2.44%	41
Finnishnot grpmax-eligible	2.41%	42
African / African-American	1.84%	54

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.Asp195His
Coding: c.583G>C
MANE Select: NM_001329752
dbSNP: rs75086964
Type: single nucleotide variant
Location: chr2:70297444 (GRCh38)
Structure: AlphaFold pLDDT 95.42
Residue 88 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.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-asp195his (accessed [today's date]).

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