Is TRNT1 p.Pro217Ser (c.649C>T) pathogenic?

TRNT1 p.Pro217Ser (c.649C>T) is classified Uncertain significance in TRNT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-08). AlphaMissense: likely benign (0.0822); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with TRNT1 p.Pro217Ser (c.649C>T)?

TRNT1 p.Pro217Ser (c.649C>T) is associated with Inborn genetic diseases, congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome (ClinVar).

How common is TRNT1 p.Pro217Ser (c.649C>T) in the general population?

TRNT1 p.Pro217Ser (c.649C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TRNT1 p.Pro217Ser (c.649C>T)?

AlphaMissense predicts likely benign (score 0.0822) — an in-silico prediction, not a clinical call.

TRNT1 p.Pro217Ser

c.649C>T · rs775586520 · VCV1426653

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0822 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0822	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -8.22	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 -0.019	GERP -1.2
Regional constraint	o/e 1.25	unconstrained · MANE · 19 kb · p 1e-08 · regional, not allelic
Overall
CADD	11.77	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,982 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,696 alleles · very rare exomes 3/1,461,530 · genomes 0/152,166 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,982
European (non-Finnish)	0.00017%	589,911

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.Pro217Ser
Coding: c.649C>T
MANE Select: NM_182916
dbSNP: rs775586520
Type: single nucleotide variant
Location: chr3:3146470 (GRCh38)
Gene constraint: LOEUF 1.232 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.00 · 3 PDB
Residue 217: a UniProt-annotated variant site (in sifd; uncertain significance); an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

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
TRNT1 p.Ala358Gly 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-pro217ser (accessed [today's date]).

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