Is TERF2IP p.Leu45= (c.135C>T) pathogenic?

TERF2IP p.Leu45= (c.135C>T) is classified Likely benign in TERF2IP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-11). Very rare (popmax 0.00501%, amr).

How common is TERF2IP p.Leu45= (c.135C>T) in the general population?

TERF2IP p.Leu45= (c.135C>T) is very rare (popmax 0.00501%, amr) (gnomAD).

TERF2IP p.Leu45=

c.135C>T · rs377280194 · VCV1770792

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.92	GERP 0.97, phastCons 1
Overall
CADD	14.15	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00501% Admixed American · 3/59,926 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000434% 7/1,612,596 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00501%	19,975
European (non-Finnish)	0.000339%	294,904

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: TERF2IP
Protein: p.Leu45=
Coding: c.135C>T
MANE Select: NM_018975
dbSNP: rs377280194
Type: single nucleotide variant
Location: chr16:75648017 (GRCh38)
Gene constraint: LOEUF 1.45 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.76 · 5 PDB
Residue 45: an α-helix

Full TERF2IP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TERF2IP p.Leu45Ile Uncertain significance ★ ⚠ same residue
TERF2IP p.Leu45Phe Uncertain significance ★ ⚠ same residue
TERF2IP p.Leu45Val Uncertain significance ★ ⚠ same residue
TERF2IP p.Ala123Gly Uncertain significance ★★ ⚠ same type
TERF2IP p.Ala200Gly Uncertain significance ★★ ⚠ same type
TERF2IP p.Ala387Val Uncertain significance ★★ ⚠ same type
TERF2IP p.Ala61Thr Uncertain significance ★★ ⚠ same type
TERF2IP p.Ala65Thr Uncertain significance ★★ ⚠ 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/terf2ip-p-leu45 (accessed [today's date]).

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