Is MRTFA p.Val533Leu (c.1597G>C) pathogenic?

MRTFA p.Val533Leu (c.1597G>C) is classified Uncertain significance in MRTFA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-06). AlphaMissense: likely benign (0.1948); Very rare (popmax 0.0093%, eas).

How common is MRTFA p.Val533Leu (c.1597G>C) in the general population?

MRTFA p.Val533Leu (c.1597G>C) is very rare (popmax 0.0093%, eas) (gnomAD).

What do computational predictors say about MRTFA p.Val533Leu (c.1597G>C)?

AlphaMissense predicts likely benign (score 0.1948) — an in-silico prediction, not a clinical call.

MRTFA p.Val533Leu

c.1597G>C · rs758579932 · VCV1683071

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1948 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0093%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1948	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -7.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 1.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 13 kb · p 0.043 · regional, not allelic
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V433L vs ClinVar V533L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0093% East Asian · 4/43,026 alleles

Filtering AF 0.00317% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.002%

Overall 0.00328% 52/1,587,022 alleles · very rare exomes 45/1,434,872 · genomes 7/152,150 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0093%	10,757
Remaining individualsnot grpmax-eligible	0.00815%	12,269
South Asian	0.0068%	14,716
European (non-Finnish)	0.003%	33,333
Admixed American	0.00176%	56,928
African / African-American	0.00135%	73,984

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: MRTFA
Protein: p.Val533Leu
Coding: c.1597G>C
MANE Select: NM_020831
dbSNP: rs758579932
Type: single nucleotide variant
Location: chr22:40419141 (GRCh38)
Gene constraint: LOEUF 0.389 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.59 · 2 PDB

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

Similar variants

MRTFA p.Val533= Likely benign ★ same residue
MRTFA p.Val533del Uncertain significance ★ same residue
MRTFA p.Ala352Thr Uncertain significance ★★ ⚠ same type
MRTFA p.Ala360Thr Uncertain significance ★★ ⚠ same type
MRTFA p.Ala429Ser Uncertain significance ★★ ⚠ same type
MRTFA p.Ala479Gly Uncertain significance ★★ ⚠ same type
MRTFA p.Ala479Val Uncertain significance ★★ ⚠ same type
MRTFA p.Ala534Thr 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/mrtfa-p-val533leu (accessed [today's date]).

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