Is TRNT1 p.Pro356Ser (c.1066C>T) pathogenic?

TRNT1 p.Pro356Ser (c.1066C>T) is classified Conflicting classifications of pathogenicity in TRNT1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-23). AlphaMissense: likely benign (0.0768); Ultra-rare (popmax 0.0173%, afr); Associated with congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome.

How common is TRNT1 p.Pro356Ser (c.1066C>T) in the general population?

TRNT1 p.Pro356Ser (c.1066C>T) is ultra-rare (popmax 0.0173%, afr) (gnomAD).

What do computational predictors say about TRNT1 p.Pro356Ser (c.1066C>T)?

AlphaMissense predicts likely benign (score 0.0768) — an in-silico prediction, not a clinical call.

TRNT1 p.Pro356Ser

Q: What condition is associated with TRNT1 p.Pro356Ser (c.1066C>T)?

TRNT1 p.Pro356Ser (c.1066C>T) is associated with congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome (ClinVar).

Q: How is Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1066C>T · rs375726663 · VCV662543

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0768 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome

Computational evidence

Protein change
AlphaMissense	0.0768	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -7.17	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 -0.19	GERP -3.9
Regional constraint	o/e 1.25	unconstrained · MANE · 19 kb · p 1e-08 · regional, not allelic
Overall
CADD	4.279	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0173% African / African-American · 13/74,950 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00812%

Overall 0.00124% 20/1,611,812 alleles · ultra-rare exomes 10/1,459,592 · genomes 10/152,220 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0173%	5,765
Remaining individualsnot grpmax-eligible	0.00961%	10,401
European (non-Finnish)	8.48e-05%	1,178,768

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: TRNT1
Protein: p.Pro356Ser
Coding: c.1066C>T
MANE Select: NM_182916
dbSNP: rs375726663
Type: single nucleotide variant
Location: chr3:3147915 (GRCh38)
Gene constraint: LOEUF 1.232 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.00 · 3 PDB
Residue 356: a UniProt-annotated variant site (in sifd; uncertain significance)

Full TRNT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

TRNT1 p.Pro356= Likely benign ★ same residue
TRNT1 p.Arg190Ile Pathogenic ★★ same condition
TRNT1 p.Arg412Ter Pathogenic/Likely pathogenic ★★ same condition
TRNT1 p.Glu277Ter Pathogenic/Likely pathogenic ★★ same condition
TRNT1 p.Ile223Thr Pathogenic ★★ same condition
TRNT1 p.Lys416Glu Pathogenic/Likely pathogenic ★★ ⚠ same condition
TRNT1 p.Ala273Gly Uncertain significance ★★ ⚠ same condition
TRNT1 p.Ala316Thr 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/trnt1-p-pro356ser (accessed [today's date]).

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