Is TINF2 p.Ser448Phe (c.1343C>T) pathogenic?

TINF2 p.Ser448Phe (c.1343C>T) is classified Uncertain significance in TINF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-17). AlphaMissense: likely benign (0.1378); Very rare (popmax 0.0011%, sas); Associated with dyskeratosis congenita.

What condition is associated with TINF2 p.Ser448Phe (c.1343C>T)?

TINF2 p.Ser448Phe (c.1343C>T) is associated with dyskeratosis congenita (ClinVar).

How common is TINF2 p.Ser448Phe (c.1343C>T) in the general population?

TINF2 p.Ser448Phe (c.1343C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Dyskeratosis congenita inherited?

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

What do computational predictors say about TINF2 p.Ser448Phe (c.1343C>T)?

AlphaMissense predicts likely benign (score 0.1378) — an in-silico prediction, not a clinical call.

TINF2 p.Ser448Phe

c.1343C>T · rs757192833 · VCV1954043

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1378 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dyskeratosis congenita

Computational evidence

Protein change
AlphaMissense	0.1378	likely benign
REVEL	0.285	benign-leaning
SaProt	LLR -7.63	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 2.7	GERP 0.66, phastCons 0.51
Regional constraint	o/e 0.95	unconstrained · MANE · 795 bp · p 0.5 · regional, not allelic
Overall
CADD	20.2	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 0.0011% South Asian · 1/91,080 alleles

Overall 6.2e-05% 1/1,614,186 alleles · very rare exomes 1/1,461,882 · genomes 0/152,304 · joint denominator

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: TINF2
Protein: p.Ser448Phe
Coding: c.1343C>T
MANE Select: NM_001099274
dbSNP: rs757192833
Type: single nucleotide variant
Location: chr14:24239810 (GRCh38)
Gene constraint: LOEUF 0.688 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.42 · 3 PDB

Full TINF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

dyskeratosis congenita — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Dyskeratosis congenita (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

TINF2 p.Ser448Cys Uncertain significance ★ ⚠ same residue
TINF2 p.Arg282Cys Pathogenic ★★ ⚠ same condition
TINF2 p.Arg282His Pathogenic ★★ ⚠ same condition
TINF2 p.Leu287Pro Likely pathogenic ★★ ⚠ same condition
TINF2 c.1061+1G>T Uncertain significance ★★ same condition
TINF2 c.1130-1G>T Uncertain significance ★★ same condition
TINF2 p.Ala10Ser Uncertain significance ★★ ⚠ same condition
TINF2 p.Ala124Pro 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/tinf2-p-ser448phe (accessed [today's date]).

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