Is TERF2IP p.Arg378Ser (c.1134A>C) pathogenic?

TERF2IP p.Arg378Ser (c.1134A>C) is classified Uncertain significance in TERF2IP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-02). AlphaMissense: likely pathogenic (0.8231); Ultra-rare (popmax 0.0111%, nfe).

How common is TERF2IP p.Arg378Ser (c.1134A>C) in the general population?

TERF2IP p.Arg378Ser (c.1134A>C) is ultra-rare (popmax 0.0111%, nfe) (gnomAD).

What do computational predictors say about TERF2IP p.Arg378Ser (c.1134A>C)?

AlphaMissense predicts likely pathogenic (score 0.8231) — an in-silico prediction, not a clinical call.

TERF2IP p.Arg378Ser

c.1134A>C · rs138458227 · VCV1729234

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8231 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8231	likely pathogenic
REVEL	0.226	benign-leaning
SaProt	LLR -9.84	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -3.3, phastCons 0.97
Regional constraint	o/e 1.11	unconstrained · MANE · 8,725 bp · p 0.011 · regional, not allelic
Overall
CADD	14.78	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 0.0111% European (non-Finnish) · 131/1,179,822 alleles

Filtering AF 0.00953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00896%

Overall 0.00905% 146/1,613,684 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0111%	9,006
Remaining individualsnot grpmax-eligible	0.0096%	10,413
African / African-American	0.00934%	10,704
Admixed American	0.00334%	29,982

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.Arg378Ser
Coding: c.1134A>C
MANE Select: NM_018975
dbSNP: rs138458227
Type: single nucleotide variant
Location: chr16:75656545 (GRCh38)
Gene constraint: LOEUF 1.45 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.76 · 5 PDB
Residue 378: an α-helix

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

Similar variants

TERF2IP p.Arg378Gly Uncertain significance ★ ⚠ same residue
TERF2IP p.Arg378Lys 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

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-arg378ser (accessed [today's date]).

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