Is TERF2 p.Ser497= (c.1491C>T) pathogenic?

TERF2 p.Ser497= (c.1491C>T) is classified Likely benign in TERF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-28). Very rare (popmax 0.00669%, eas).

How common is TERF2 p.Ser497= (c.1491C>T) in the general population?

TERF2 p.Ser497= (c.1491C>T) is very rare (popmax 0.00669%, eas) (gnomAD).

TERF2 p.Ser497=

c.1491C>T · VCV4930658

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

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 0.083	GERP -4.6, phastCons 0.38
Overall
CADD	6.328	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% East Asian · 3/44,840 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.00285% 46/1,611,450 alleles · very rare exomes 43/1,459,262 · genomes 3/152,188 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0465%	2,153
East Asiangrpmax	0.00669%	14,947
South Asian	0.00111%	90,376
European (non-Finnish)	0.0011%	90,713

Remaining individuals 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: TERF2
Protein: p.Ser497=
Coding: c.1491C>T
MANE Select: NM_005652
Type: single nucleotide variant
Location: chr16:69357036 (GRCh38)
Gene constraint: LOEUF 0.444 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.36 · 18 PDB
Residue 497: the hth myb-type domain; an α-helix

Full TERF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TERF2 c.1341-42T>C Benign ★★ same type
TERF2 c.1426+95C>T Benign ★★ same type
TERF2 c.380-5C>T Benign ★★ same type
TERF2 c.840+145C>T Benign ★★ same type
TERF2 c.947+27G>A Benign ★★ same type
TERF2 c.*142G>A Benign ★★ same type
TERF2 c.*159C>T Benign ★★ same type
TERF2 c.*220A>G Benign ★★ 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/terf2-p-ser497 (accessed [today's date]).

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