Is TERF2IP p.Lys324Glu (c.970A>G) pathogenic?

TERF2IP p.Lys324Glu (c.970A>G) is classified Benign in TERF2IP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1); Common (popmax 6.48%, mid) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about TERF2IP p.Lys324Glu (c.970A>G)?

AlphaMissense predicts likely benign (score 0.1) — an in-silico prediction, not a clinical call.

TERF2IP p.Lys324Glu

Q: How common is TERF2IP p.Lys324Glu (c.970A>G) in the general population?

TERF2IP p.Lys324Glu (c.970A>G) is common (popmax 6.48%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.970A>G · rs4888444 · VCV1697661

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.48%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -5.30	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 9.2	GERP 1.8, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 8,725 bp · p 0.011 · regional, not allelic
Overall
CADD	20.5	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 6.48% Middle Eastern · 393/6,062 alleles

Filtering AF 5.95% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.75%

Overall 4.11% 66,325/1,614,148 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	10.3%	10
Middle Easterngrpmax	6.48%	15
Ashkenazi Jewishnot grpmax-eligible	6.04%	17
South Asian	4.95%	20
European (non-Finnish)	4.6%	22
Remaining individualsnot grpmax-eligible	3.95%	25
Admixed American	2.2%	45
Finnishnot grpmax-eligible	1.52%	66
African / African-American	0.722%	138
East Asian	0.0201%	4,987

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Lys324Glu
Coding: c.970A>G
MANE Select: NM_018975
dbSNP: rs4888444
Type: single nucleotide variant
Location: chr16:75656381 (GRCh38)
Gene constraint: LOEUF 1.45 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.76 · 5 PDB
Residue 324: a UniProt-annotated variant site (in); an α-helix

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

Similar variants

TERF2IP p.Lys324Thr Uncertain significance ★ ⚠ same residue
TERF2IP p.Lys324= Likely benign ★ 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

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-lys324glu (accessed [today's date]).

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