Is TERF2IP p.Ala345Pro (c.1033G>C) pathogenic?

TERF2IP p.Ala345Pro (c.1033G>C) is classified Uncertain significance in TERF2IP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-14). AlphaMissense: likely pathogenic (0.8427); Very rare (popmax 0.0011%, sas).

How common is TERF2IP p.Ala345Pro (c.1033G>C) in the general population?

TERF2IP p.Ala345Pro (c.1033G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about TERF2IP p.Ala345Pro (c.1033G>C)?

AlphaMissense predicts likely pathogenic (score 0.8427) — an in-silico prediction, not a clinical call.

TERF2IP p.Ala345Pro

c.1033G>C · rs2507089669 · VCV2563467

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8427 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8427	likely pathogenic
REVEL	0.128	moderately benign-leaning
SaProt	LLR -10.62	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.9, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 8,725 bp · p 0.011 · regional, not allelic
Overall
CADD	26.6	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

Grpmax group 0.0011% South Asian · 1/91,084 alleles

Overall 0.000137% 2/1,461,890 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,084
European (non-Finnish)	8.47e-05%	1,180,034

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.Ala345Pro
Coding: c.1033G>C
MANE Select: NM_018975
dbSNP: rs2507089669
Type: single nucleotide variant
Location: chr16:75656444 (GRCh38)
Gene constraint: LOEUF 1.45 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.76 · 5 PDB
Residue 345: an α-helix

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

Similar variants

TERF2IP p.Ala345Ser 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
TERF2IP p.Arg133Gln Uncertain significance ★★ ⚠ same type
TERF2IP p.Arg378Ser 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-ala345pro (accessed [today's date]).

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