Is MRTFA p.Ser435Leu (c.1304C>T) pathogenic?

MRTFA p.Ser435Leu (c.1304C>T) is classified Uncertain significance in MRTFA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-15). AlphaMissense: likely benign (0.0739); Very rare (popmax 0.00915%, nfe); Associated with immunodeficiency 66.

What condition is associated with MRTFA p.Ser435Leu (c.1304C>T)?

MRTFA p.Ser435Leu (c.1304C>T) is associated with immunodeficiency 66 (ClinVar).

How common is MRTFA p.Ser435Leu (c.1304C>T) in the general population?

MRTFA p.Ser435Leu (c.1304C>T) is very rare (popmax 0.00915%, nfe) (gnomAD).

What do computational predictors say about MRTFA p.Ser435Leu (c.1304C>T)?

AlphaMissense predicts likely benign (score 0.0739) — an in-silico prediction, not a clinical call.

MRTFA p.Ser435Leu

c.1304C>T · rs767517879 · VCV1683092

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0739 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00915%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 66

Computational evidence

Protein change
AlphaMissense	0.0739	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -8.80	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 3.5	GERP -1.3, phastCons 0.66
Regional constraint	o/e 1.06	unconstrained · MANE · 13 kb · p 0.043 · regional, not allelic
Overall
CADD	18.25	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 S335L vs ClinVar S435L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00915% European (non-Finnish) · 108/1,180,044 alleles

Filtering AF 0.00774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00719%

Overall 0.00688% 111/1,613,638 alleles · very rare exomes 102/1,461,372 · genomes 9/152,266 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00915%	10,926
Remaining individualsnot grpmax-eligible	0.0048%	20,827

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.Ser435Leu
Coding: c.1304C>T
MANE Select: NM_020831
dbSNP: rs767517879
Type: single nucleotide variant
Location: chr22:40420454 (GRCh38)
Gene constraint: LOEUF 0.389 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.59 · 2 PDB
Residue 335 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.Val553Met 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-ser435leu (accessed [today's date]).

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