Is MRTFA p.Ala669Thr (c.2005G>A) pathogenic?

MRTFA p.Ala669Thr (c.2005G>A) is classified Benign/Likely benign in MRTFA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0713); Common (popmax 42.1%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about MRTFA p.Ala669Thr (c.2005G>A)?

AlphaMissense predicts likely benign (score 0.0713) — an in-silico prediction, not a clinical call.

MRTFA p.Ala669Thr

Q: How common is MRTFA p.Ala669Thr (c.2005G>A) in the general population?

MRTFA p.Ala669Thr (c.2005G>A) is common (popmax 42.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2005G>A · rs144888766 · VCV1169755

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0713 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 42.1%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0713	likely benign
REVEL	0.003	strongly benign-leaning
SaProt	LLR -7.66	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 -0.8	GERP -0.59
Regional constraint	o/e 1.06	unconstrained · MANE · 13 kb · p 0.043 · regional, not allelic
Overall
CADD	2.072	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A569T vs ClinVar A669T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 42.1% African / African-American · 5,689/13,508 alleles

Filtering AF 41.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 40.8%

Overall 5.12% 6,823/133,252 alleles · common exomes 3,346/123,924 · genomes 3,477/9,328 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	42.1%	2
Remaining individualsnot grpmax-eligible	6.68%	15
Middle Eastern	6.31%	16
Admixed American	5.79%	17
Ashkenazi Jewishnot grpmax-eligible	1.07%	93
European (non-Finnish)	0.414%	241
South Asian	0.211%	473
East Asian	0.0917%	1,091

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.Ala669Thr
Coding: c.2005G>A
MANE Select: NM_020831
dbSNP: rs144888766
Type: single nucleotide variant
Location: chr22:40418733 (GRCh38)
Gene constraint: LOEUF 0.389 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.59 · 2 PDB
Residue 569 UniProt numbering: the 'disordered' region

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

Similar variants

MRTFA p.Ala669Ser Uncertain significance ★ ⚠ same residue
MRTFA p.Ala669Val Conflicting classifications of pathogenicity ★ ⚠ 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-ala669thr (accessed [today's date]).

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