Is TINF2 p.Ala99Pro (c.295G>C) pathogenic?

TINF2 p.Ala99Pro (c.295G>C) is classified Uncertain significance in TINF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-12). AlphaMissense: ambiguous (0.5502); Absent from gnomAD v4.1; Associated with dyskeratosis congenita.

What condition is associated with TINF2 p.Ala99Pro (c.295G>C)?

TINF2 p.Ala99Pro (c.295G>C) is associated with dyskeratosis congenita (ClinVar).

How common is TINF2 p.Ala99Pro (c.295G>C) in the general population?

TINF2 p.Ala99Pro (c.295G>C) is absent from gnomAD v4.1 (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.Ala99Pro (c.295G>C)?

AlphaMissense predicts ambiguous (score 0.5502) — an in-silico prediction, not a clinical call.

TINF2 p.Ala99Pro

c.295G>C · rs761179618 · VCV2876815

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5502 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

dyskeratosis congenita

Computational evidence

Protein change
AlphaMissense	0.5502	ambiguous
REVEL	0.055	moderately benign-leaning
SaProt	LLR -10.55	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.4	GERP -0.51, phastCons 0.017
Regional constraint	o/e 0.91	unconstrained · MANE · 1,695 bp · p 0.11 · regional, not allelic
Overall
CADD	19.89	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TINF2
Protein: p.Ala99Pro
Coding: c.295G>C
MANE Select: NM_001099274
dbSNP: rs761179618
Type: single nucleotide variant
Location: chr14:24241892 (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.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
TINF2 p.Ala124Val 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-ala99pro (accessed [today's date]).

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