Is TEC p.Glu446Ala (c.1337A>C) pathogenic?

TEC p.Glu446Ala (c.1337A>C) is classified Uncertain significance in TEC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely benign (0.2021); Ultra-rare (popmax 0.0227%, afr).

How common is TEC p.Glu446Ala (c.1337A>C) in the general population?

TEC p.Glu446Ala (c.1337A>C) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about TEC p.Glu446Ala (c.1337A>C)?

AlphaMissense predicts likely benign (score 0.2021) — an in-silico prediction, not a clinical call.

TEC p.Glu446Ala

c.1337A>C · VCV4182096

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2021 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2021	likely benign
REVEL	0.286	benign-leaning
SaProt	LLR -5.59	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.42 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 12 kb · p 3.1e-07 · regional, not allelic
Overall
CADD	23.9	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 0.0227% African / African-American · 17/74,906 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.0013% 21/1,614,016 alleles · ultra-rare exomes 12/1,461,868 · genomes 9/152,148 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,406
South Asian	0.0022%	45,543
Admixed American	0.00167%	59,996
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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: TEC
Protein: p.Glu446Ala
Coding: c.1337A>C
MANE Select: NM_003215
Type: single nucleotide variant
Location: chr4:48145212 (GRCh38)
Gene constraint: LOEUF 0.89 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.48 · 1 PDB
Residue 446: the protein kinase domain

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

Similar variants

TEC c.496-1G>A Likely pathogenic ★ same type
TEC p.Ala500Val Uncertain significance ★ ⚠ same type
TEC p.Arg202Ser Uncertain significance ★ ⚠ same type
TEC p.Arg262Leu Uncertain significance ★ ⚠ same type
TEC p.Arg29Gly Uncertain significance ★ ⚠ same type
TEC p.Arg342Gln Uncertain significance ★ ⚠ same type
TEC p.Arg390Gln Uncertain significance ★ same type
TEC p.Arg617Cys 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/tec-p-glu446ala (accessed [today's date]).

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