Is TLL2 p.Ile703Ser (c.2108T>G) pathogenic?

TLL2 p.Ile703Ser (c.2108T>G) is classified Uncertain significance in TLL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-20). AlphaMissense: likely pathogenic (0.752); Very rare (popmax 0.00501%, amr).

How common is TLL2 p.Ile703Ser (c.2108T>G) in the general population?

TLL2 p.Ile703Ser (c.2108T>G) is very rare (popmax 0.00501%, amr) (gnomAD).

What do computational predictors say about TLL2 p.Ile703Ser (c.2108T>G)?

AlphaMissense predicts likely pathogenic (score 0.752) — an in-silico prediction, not a clinical call.

TLL2 p.Ile703Ser

c.2108T>G · rs753228735 · VCV2366108

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.752 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.752	likely pathogenic
REVEL	0.634	indeterminate
SaProt	LLR -14.76	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 146 kb · p 0.9 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00501% Admixed American · 3/59,908 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.0013% 21/1,612,930 alleles · very rare exomes 18/1,460,720 · genomes 3/152,210 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00501%	19,969
European (non-Finnish)	0.00153%	65,520

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: TLL2
Protein: p.Ile703Ser
Coding: c.2108T>G
MANE Select: NM_012465
dbSNP: rs753228735
Type: single nucleotide variant
Location: chr10:96384673 (GRCh38)
Gene constraint: LOEUF 0.99 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.98
Residue 703: the cub 3 domain

Full TLL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TLL2 p.Ala737Thr Uncertain significance ★★ ⚠ same type
TLL2 p.Pro914Leu Uncertain significance ★★ ⚠ same type
TLL2 p.Arg446His Benign ★★ same type
TLL2 p.Gly366Arg Benign ★★ same type
TLL2 p.Phe751Leu Benign ★★ same type
TLL2 p.Thr495= Benign ★★ same type
TLL2 p.Ala302Thr Uncertain significance ★ ⚠ same type
TLL2 p.Ala342Thr 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/tll2-p-ile703ser (accessed [today's date]).

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