Is TLE2 p.Gly316Arg (c.946G>A) pathogenic?

TLE2 p.Gly316Arg (c.946G>A) is classified Likely benign in TLE2 (ClinVar, Single submitter, 3 submitters). AlphaMissense: likely benign (0.2967); Low-frequency (popmax 1.26%, nfe); Associated with neutropenia.

What condition is associated with TLE2 p.Gly316Arg (c.946G>A)?

TLE2 p.Gly316Arg (c.946G>A) is associated with neutropenia, lymphopenia (ClinVar).

How common is TLE2 p.Gly316Arg (c.946G>A) in the general population?

TLE2 p.Gly316Arg (c.946G>A) is low-frequency (popmax 1.26%, nfe) (gnomAD).

What do computational predictors say about TLE2 p.Gly316Arg (c.946G>A)?

AlphaMissense predicts likely benign (score 0.2967) — an in-silico prediction, not a clinical call.

TLE2 p.Gly316Arg

c.946G>A · rs201317355 · VCV1679861

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2967 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.26%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

neutropenia

Computational evidence

Protein change
AlphaMissense	0.2967	likely benign
REVEL	0.348	indeterminate
SaProt	LLR -6.72	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 31 kb · p 0.36 · regional, not allelic
Overall
CADD	26.6	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 1.26% European (non-Finnish) · 14,848/1,179,014 alleles

Filtering AF 1.24% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.24%

Overall 1.02% 16,487/1,610,450 alleles · low-frequency exomes 15,511/1,458,254 · genomes 976/152,196 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.26%	79
Ashkenazi Jewishnot grpmax-eligible	1.19%	84
Remaining individualsnot grpmax-eligible	0.798%	125
Finnishnot grpmax-eligible	0.361%	277
Admixed American	0.329%	304
South Asian	0.238%	419
African / African-American	0.193%	517
Middle Eastern	0.0987%	1,013

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.Gly316Arg
Coding: c.946G>A
MANE Select: NM_003260
dbSNP: rs201317355
Type: single nucleotide variant
Location: chr19:3011088 (GRCh38)
Gene constraint: LOEUF 1.02 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.40
Residue 316: the 'sp domain' region; the 'disordered' region

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.Ser705Asn 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-gly316arg (accessed [today's date]).

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