Is MRTFA p.Val553Met (c.1657G>A) pathogenic?

MRTFA p.Val553Met (c.1657G>A) is classified Uncertain significance in MRTFA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-20). AlphaMissense: likely benign (0.198); Ultra-rare (popmax 0.0494%, mid); Associated with immunodeficiency 66.

What condition is associated with MRTFA p.Val553Met (c.1657G>A)?

MRTFA p.Val553Met (c.1657G>A) is associated with immunodeficiency 66 (ClinVar).

How common is MRTFA p.Val553Met (c.1657G>A) in the general population?

MRTFA p.Val553Met (c.1657G>A) is ultra-rare (popmax 0.0494%, mid) (gnomAD).

What do computational predictors say about MRTFA p.Val553Met (c.1657G>A)?

AlphaMissense predicts likely benign (score 0.198) — an in-silico prediction, not a clinical call.

MRTFA p.Val553Met

c.1657G>A · rs543904613 · VCV1683058

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.198 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 66

Computational evidence

Protein change
AlphaMissense	0.198	likely benign
REVEL	0.193	benign-leaning
SaProt	LLR -7.58	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 7.7	GERP 0.38, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 13 kb · p 0.043 · regional, not allelic
Overall
CADD	23.1	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 V453M vs ClinVar V553M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0494% Middle Eastern · 3/6,070 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00717%

Overall 0.00399% 64/1,605,216 alleles · ultra-rare exomes 60/1,453,174 · genomes 4/152,042 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0494%	2,023
Remaining individualsnot grpmax-eligible	0.00966%	10,353
Admixed American	0.00847%	11,804
European (non-Finnish)	0.00399%	25,033
East Asian	0.00225%	44,390
South Asian	0.00222%	45,060

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.Val553Met
Coding: c.1657G>A
MANE Select: NM_020831
dbSNP: rs543904613
Type: single nucleotide variant
Location: chr22:40419081 (GRCh38)
Gene constraint: LOEUF 0.389 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.59 · 2 PDB
Residue 453 UniProt numbering: the 'disordered' region

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

Disease context

immunodeficiency 66 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MRTFA p.Ala636Val Uncertain significance ★★ ⚠ same condition
MRTFA p.Arg639His Uncertain significance ★★ ⚠ same condition
MRTFA p.Asp942Asn Uncertain significance ★★ ⚠ same condition
MRTFA p.Met976Ile Uncertain significance ★★ ⚠ same condition
MRTFA p.Ser435Leu Uncertain significance ★★ ⚠ same condition
MRTFA p.Val675Met Uncertain significance ★★ ⚠ same condition
MRTFA p.Leu749Ile Benign/Likely benign ★★ same condition
MRTFA p.Gly401Arg 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/mrtfa-p-val553met (accessed [today's date]).

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