Is TRRAP p.Phe541Leu (c.1623C>G) pathogenic?

TRRAP p.Phe541Leu (c.1623C>G) is classified Conflicting classifications of pathogenicity in TRRAP (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-28). AlphaMissense: likely pathogenic (0.9869); Very rare (popmax 0.00669%, afr); Associated with Inborn genetic diseases.

What condition is associated with TRRAP p.Phe541Leu (c.1623C>G)?

TRRAP p.Phe541Leu (c.1623C>G) is associated with Inborn genetic diseases (ClinVar).

How common is TRRAP p.Phe541Leu (c.1623C>G) in the general population?

TRRAP p.Phe541Leu (c.1623C>G) is very rare (popmax 0.00669%, afr) (gnomAD).

What do computational predictors say about TRRAP p.Phe541Leu (c.1623C>G)?

AlphaMissense predicts likely pathogenic (score 0.9869) — an in-silico prediction, not a clinical call.

TRRAP p.Phe541Leu

c.1623C>G · rs373918715 · VCV1536266

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9869 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, afr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9869	likely pathogenic
REVEL	0.244	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -0.078, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 293 bp · p 0.39 · regional, not allelic
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% African / African-American · 5/74,716 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.000435% 7/1,610,390 alleles · very rare exomes 5/1,458,830 · genomes 2/151,560 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00669%	14,943
Remaining individualsnot grpmax-eligible	0.0016%	62,448
European (non-Finnish)	8.48e-05%	1,179,903

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.Phe541Leu
Coding: c.1623C>G
MANE Select: NM_001375524
dbSNP: rs373918715
Type: single nucleotide variant
Location: chr7:98910328 (GRCh38)
Gene constraint: LOEUF 0.115 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 541: an α-helix; the 'disordered' region

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 p.Phe541= Likely benign ★ same residue
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

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-phe541leu (accessed [today's date]).

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