Is TIMCC p.Ala239Pro (c.715G>C) pathogenic?

TIMCC p.Ala239Pro (c.715G>C) is classified Likely benign in TIMCC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-26). AlphaMissense: likely pathogenic (0.8588); Low-frequency (popmax 1.93%, amr).

How common is TIMCC p.Ala239Pro (c.715G>C) in the general population?

TIMCC p.Ala239Pro (c.715G>C) is low-frequency (popmax 1.93%, amr) (gnomAD).

What do computational predictors say about TIMCC p.Ala239Pro (c.715G>C)?

AlphaMissense predicts likely pathogenic (score 0.8588) — an in-silico prediction, not a clinical call.

TIMCC p.Ala239Pro

c.715G>C · VCV4955455

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8588 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.93%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8588	likely pathogenic
REVEL	0.033	moderately benign-leaning
SaProt	LLR -12.12	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP -1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 4,719 bp · p 0.74 · regional, not allelic
Overall
CADD	23.6	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 A132P vs ClinVar A239P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.93% Admixed American · 832/43,154 alleles

Filtering AF 1.82% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.78%

Overall 0.415% 5,867/1,413,628 alleles · low-frequency exomes 3,650/1,302,456 · genomes 2,217/111,172 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	5.04%	20
Admixed Americangrpmax	1.93%	52
East Asian	0.861%	116
African / African-American	0.708%	141
Ashkenazi Jewishnot grpmax-eligible	0.686%	146
South Asian	0.508%	197
Finnishnot grpmax-eligible	0.419%	239
Remaining individualsnot grpmax-eligible	0.409%	245
European (non-Finnish)	0.307%	326
Middle Eastern	0.201%	498

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.Ala239Pro
Coding: c.715G>C
MANE Select: NM_001329752
Type: single nucleotide variant
Location: chr2:70297312 (GRCh38)
Structure: AlphaFold pLDDT 95.42
Residue 132 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-ala239pro (accessed [today's date]).

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