Is TRRAP p.Val1975Leu (c.5923G>C) pathogenic?

TRRAP p.Val1975Leu (c.5923G>C) is classified Uncertain significance in TRRAP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-19). AlphaMissense: likely pathogenic (0.8898); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with TRRAP p.Val1975Leu (c.5923G>C)?

TRRAP p.Val1975Leu (c.5923G>C) is associated with Inborn genetic diseases (ClinVar).

How common is TRRAP p.Val1975Leu (c.5923G>C) in the general population?

TRRAP p.Val1975Leu (c.5923G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about TRRAP p.Val1975Leu (c.5923G>C)?

AlphaMissense predicts likely pathogenic (score 0.8898) — an in-silico prediction, not a clinical call.

TRRAP p.Val1975Leu

c.5923G>C · VCV3607200

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8898 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8898	likely pathogenic
REVEL	0.384	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 27 kb · p 6.5e-16 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V1968L vs ClinVar V1975L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,046 alleles

Overall 0.000124% 2/1,613,440 alleles · very rare exomes 2/1,461,080 · genomes 0/152,360 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,046
European (non-Finnish)	8.48e-05%	1,179,537

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: TRRAP
Protein: p.Val1975Leu
Coding: c.5923G>C
MANE Select: NM_001375524
Type: single nucleotide variant
Location: chr7:98955290 (GRCh38)
Gene constraint: LOEUF 0.115 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRRAP c.8247+5G>T Uncertain significance ★★ same condition
TRRAP p.Ala1055Thr Uncertain significance ★★ same condition
TRRAP p.Ala1880Val Uncertain significance ★★ ⚠ same condition
TRRAP p.Ala1895Val Uncertain significance ★★ same condition
TRRAP p.Ala1995Thr Uncertain significance ★★ same condition
TRRAP p.Ala2656Thr Uncertain significance ★★ ⚠ same condition
TRRAP p.Ala322Ser Uncertain significance ★★ ⚠ same condition
TRRAP p.Ala3616Thr Uncertain significance ★★ ⚠ same condition

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/trrap-p-val1975leu (accessed [today's date]).

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