Is TLE2 p.Ser705Asn (c.2114G>A) pathogenic?

TLE2 p.Ser705Asn (c.2114G>A) is classified Likely benign in TLE2 (ClinVar, Single submitter, 2 submitters). AlphaMissense: likely pathogenic (0.5716); Low-frequency (popmax 3.49%, mid); Associated with neutropenia.

What condition is associated with TLE2 p.Ser705Asn (c.2114G>A)?

TLE2 p.Ser705Asn (c.2114G>A) is associated with neutropenia, lymphopenia (ClinVar).

How common is TLE2 p.Ser705Asn (c.2114G>A) in the general population?

TLE2 p.Ser705Asn (c.2114G>A) is low-frequency (popmax 3.49%, mid) (gnomAD).

What do computational predictors say about TLE2 p.Ser705Asn (c.2114G>A)?

AlphaMissense predicts likely pathogenic (score 0.5716) — an in-silico prediction, not a clinical call.

TLE2 p.Ser705Asn

c.2114G>A · rs143713547 · VCV1679860

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5716 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.49%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neutropenia

Computational evidence

Protein change
AlphaMissense	0.5716	likely pathogenic
REVEL	0.199	benign-leaning
SaProt	LLR -12.24	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.8	phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 31 kb · p 0.36 · regional, not allelic
Overall
CADD	24.4	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 3.49% Middle Eastern · 207/5,934 alleles

Filtering AF 3.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.95%

Overall 0.49% 7,779/1,587,666 alleles · low-frequency exomes 6,507/1,435,534 · genomes 1,272/152,132 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	3.49%	29
African / African-American	1.45%	69
Finnishnot grpmax-eligible	0.955%	105
Admixed American	0.795%	126
Remaining individualsnot grpmax-eligible	0.792%	126
Ashkenazi Jewishnot grpmax-eligible	0.715%	140
European (non-Finnish)	0.391%	256
South Asian	0.227%	441

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: TLE2
Protein: p.Ser705Asn
Coding: c.2114G>A
MANE Select: NM_003260
dbSNP: rs143713547
Type: single nucleotide variant
Location: chr19:3000657 (GRCh38)
Gene constraint: LOEUF 1.02 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.40

Full TLE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neutropenia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: lymphopenia

Similar variants

TLE2 p.Gly316Arg Likely benign ★ same condition
TLE2 p.Ala110Thr Uncertain significance ★ ⚠ same type
TLE2 p.Ala133Val Uncertain significance ★ ⚠ same type
TLE2 p.Ala164Val Uncertain significance ★ ⚠ same type
TLE2 p.Ala167Val Uncertain significance ★ ⚠ same type
TLE2 p.Ala168Val Uncertain significance ★ ⚠ same type
TLE2 p.Ala187Ser Uncertain significance ★ ⚠ same type
TLE2 p.Ala187Val 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/tle2-p-ser705asn (accessed [today's date]).

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