Is TERF2 p.Ser294Arg (c.880A>C) pathogenic?

TERF2 p.Ser294Arg (c.880A>C) is classified Uncertain significance in TERF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-26). AlphaMissense: likely benign (0.2019); Absent from gnomAD v4.1; Associated with TERF2-related disorder.

What condition is associated with TERF2 p.Ser294Arg (c.880A>C)?

TERF2 p.Ser294Arg (c.880A>C) is associated with TERF2-related disorder (ClinVar).

How common is TERF2 p.Ser294Arg (c.880A>C) in the general population?

TERF2 p.Ser294Arg (c.880A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TERF2 p.Ser294Arg (c.880A>C)?

AlphaMissense predicts likely benign (score 0.2019) — an in-silico prediction, not a clinical call.

TERF2 p.Ser294Arg

c.880A>C · rs2543397056 · VCV2635710

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2019 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TERF2-related disorder

Computational evidence

Protein change
AlphaMissense	0.2019	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -7.30	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 -0.2	GERP -4, phastCons 0.001
Regional constraint	o/e 0.89	unconstrained · MANE · 11 kb · p 0.093 · regional, not allelic
Overall
CADD	8.58	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

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: TERF2
Protein: p.Ser294Arg
Coding: c.880A>C
MANE Select: NM_005652
dbSNP: rs2543397056
Type: single nucleotide variant
Location: chr16:69368443 (GRCh38)
Gene constraint: LOEUF 0.444 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.36 · 18 PDB
Residue 294: the 'disordered' region

Full TERF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

TERF2-related disorder

Similar variants

TERF2 c.1341-42T>C Benign ★★ same type
TERF2 c.1426+95C>T Benign ★★ same type
TERF2 c.380-5C>T Benign ★★ same type
TERF2 c.840+145C>T Benign ★★ same type
TERF2 c.947+27G>A Benign ★★ same type
TERF2 c.*142G>A Benign ★★ same type
TERF2 c.*159C>T Benign ★★ same type
TERF2 c.*220A>G Benign ★★ same type

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/terf2-p-ser294arg (accessed [today's date]).

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