Is TERF2 p.Ala332Val (c.995C>T) pathogenic?

TERF2 p.Ala332Val (c.995C>T) is classified Uncertain significance in TERF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-02). AlphaMissense: likely benign (0.1273); Very rare (popmax 0.00667%, afr).

How common is TERF2 p.Ala332Val (c.995C>T) in the general population?

TERF2 p.Ala332Val (c.995C>T) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about TERF2 p.Ala332Val (c.995C>T)?

AlphaMissense predicts likely benign (score 0.1273) — an in-silico prediction, not a clinical call.

TERF2 p.Ala332Val

c.995C>T · rs749655226 · VCV2493796

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1273 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1273	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -9.01	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 7.1	GERP 2.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 11 kb · p 0.093 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% African / African-American · 5/74,922 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.000496% 8/1,614,018 alleles · very rare exomes 5/1,461,824 · genomes 3/152,194 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,984
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
East Asian	0.00223%	44,888
Admixed American	0.00167%	59,988

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.Ala332Val
Coding: c.995C>T
MANE Select: NM_005652
dbSNP: rs749655226
Type: single nucleotide variant
Location: chr16:69367152 (GRCh38)
Gene constraint: LOEUF 0.444 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.36 · 18 PDB
Residue 332: 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-ala332val (accessed [today's date]).

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