Is TENM3 p.Ile1526Val (c.4576A>G) pathogenic?

TENM3 p.Ile1526Val (c.4576A>G) is classified Uncertain significance in TENM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-02). AlphaMissense: likely benign (0.0534); Ultra-rare (popmax 0.016%, afr); Associated with Inborn genetic diseases.

What condition is associated with TENM3 p.Ile1526Val (c.4576A>G)?

TENM3 p.Ile1526Val (c.4576A>G) is associated with Inborn genetic diseases (ClinVar).

How common is TENM3 p.Ile1526Val (c.4576A>G) in the general population?

TENM3 p.Ile1526Val (c.4576A>G) is ultra-rare (popmax 0.016%, afr) (gnomAD).

What do computational predictors say about TENM3 p.Ile1526Val (c.4576A>G)?

AlphaMissense predicts likely benign (score 0.0534) — an in-silico prediction, not a clinical call.

TENM3 p.Ile1526Val

c.4576A>G · VCV3325341

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0534 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0534	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -3.70	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 -0.24	GERP -2.5, phastCons 0.001
Regional constraint	o/e 0.85	unconstrained · MANE · 174 kb · p 1.9e-10 · regional, not allelic
Overall
CADD	12.36	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 0.016% African / African-American · 12/74,948 alleles

Filtering AF 0.00921% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00721%

Overall 0.000805% 13/1,613,930 alleles · ultra-rare exomes 7/1,461,684 · genomes 6/152,246 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,246
European (non-Finnish)	8.48e-05%	1,179,892

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: TENM3
Protein: p.Ile1526Val
Coding: c.4576A>G
MANE Select: NM_001080477
Type: single nucleotide variant
Location: chr4:182754943 (GRCh38)
Gene constraint: LOEUF 0.305 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.76
Residue 1526: a UniProt-annotated variant site (in mcops15)

Full TENM3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TENM3 p.Ala1056Gly Uncertain significance ★★ ⚠ same condition
TENM3 p.Ala1397Thr Uncertain significance ★★ ⚠ same condition
TENM3 p.Ala1397Val Uncertain significance ★★ ⚠ same condition
TENM3 p.Ala2168Val Uncertain significance ★★ ⚠ same condition
TENM3 p.Ala864Ser Uncertain significance ★★ ⚠ same condition
TENM3 p.Arg1341Cys Uncertain significance ★★ ⚠ same condition
TENM3 p.Arg1494Gln Uncertain significance ★★ same condition
TENM3 p.Asn601Lys Uncertain significance ★★ ⚠ same condition

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/tenm3-p-ile1526val (accessed [today's date]).

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