Is TERF2IP p.Ala249= (c.747A>C) pathogenic?

TERF2IP p.Ala249= (c.747A>C) is classified Likely benign in TERF2IP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-29). Very rare (popmax 0.00133%, afr).

How common is TERF2IP p.Ala249= (c.747A>C) in the general population?

TERF2IP p.Ala249= (c.747A>C) is very rare (popmax 0.00133%, afr) (gnomAD).

TERF2IP p.Ala249=

c.747A>C · rs1216453748 · VCV1759083

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

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 -0.029	GERP 0.47
Overall
CADD	8.193	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,944 alleles

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

Overall 0.000186% 3/1,613,898 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,944
European (non-Finnish)	0.00017%	589,957

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.Ala249=
Coding: c.747A>C
MANE Select: NM_018975
dbSNP: rs1216453748
Type: single nucleotide variant
Location: chr16:75654349 (GRCh38)
Gene constraint: LOEUF 1.45 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.76 · 5 PDB

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

Similar variants

TERF2IP p.Ala249Gly Uncertain significance ★ ⚠ same residue
TERF2IP p.Ala249Ser Uncertain significance ★ ⚠ same residue
TERF2IP p.Ala249Val 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-ala249 (accessed [today's date]).

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