Is MRTFA p.Met976Ile (c.2928G>T) pathogenic?

MRTFA p.Met976Ile (c.2928G>T) is classified Uncertain significance in MRTFA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-28). AlphaMissense: likely benign (0.129); Ultra-rare (popmax 0.0184%, nfe); Associated with immunodeficiency 66.

What condition is associated with MRTFA p.Met976Ile (c.2928G>T)?

MRTFA p.Met976Ile (c.2928G>T) is associated with immunodeficiency 66 (ClinVar).

How common is MRTFA p.Met976Ile (c.2928G>T) in the general population?

MRTFA p.Met976Ile (c.2928G>T) is ultra-rare (popmax 0.0184%, nfe) (gnomAD).

What do computational predictors say about MRTFA p.Met976Ile (c.2928G>T)?

AlphaMissense predicts likely benign (score 0.129) — an in-silico prediction, not a clinical call.

MRTFA p.Met976Ile

c.2928G>T · rs146530131 · VCV1675101

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.129 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0184%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 66

Computational evidence

Protein change
AlphaMissense	0.129	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -6.31	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.14, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 13 kb · p 0.043 · regional, not allelic
Overall
CADD	16.54	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 M876I vs ClinVar M976I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0184% European (non-Finnish) · 217/1,179,942 alleles

Filtering AF 0.0164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0156%

Overall 0.0138% 222/1,613,690 alleles · ultra-rare exomes 207/1,461,470 · genomes 15/152,220 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0184%	5,438
Remaining individualsnot grpmax-eligible	0.0032%	31,238
African / African-American	0.00267%	37,467
Admixed American	0.00167%	59,964

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.Met976Ile
Coding: c.2928G>T
MANE Select: NM_020831
dbSNP: rs146530131
Type: single nucleotide variant
Location: chr22:40411558 (GRCh38)
Gene constraint: LOEUF 0.389 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.59 · 2 PDB
Residue 876 UniProt numbering: a UniProt-annotated variant site (in imd66; probable loss-of-function; patient's dendritic cells are morphologically distinct from control dendritic cells and show reduced spreading on fibronectin-coated coverslips, a marked reduction in total f-actin staining and a complete absence of podosomes, a similar phenotype to that of thp1 cells in which mrtfa was silenced)

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.Met976Thr Uncertain significance ★★ ⚠ same residue
MRTFA p.Ala636Val Uncertain significance ★★ ⚠ same condition
MRTFA p.Arg639His Uncertain significance ★★ ⚠ same condition
MRTFA p.Asp942Asn Uncertain significance ★★ ⚠ same condition
MRTFA p.Ser435Leu Uncertain significance ★★ ⚠ same condition
MRTFA p.Val553Met Uncertain significance ★★ ⚠ same condition
MRTFA p.Val675Met Uncertain significance ★★ ⚠ same condition
MRTFA p.Leu749Ile Benign/Likely benign ★★ 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-met976ile (accessed [today's date]).

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