Is TANC2 p.Pro557Arg (c.1670C>G) pathogenic?

TANC2 p.Pro557Arg (c.1670C>G) is classified Uncertain significance in TANC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-14). AlphaMissense: ambiguous (0.5535); Ultra-rare (popmax 0.0911%, sas); Associated with intellectual developmental disorder with autistic features and language delay, with or without seizures.

How common is TANC2 p.Pro557Arg (c.1670C>G) in the general population?

TANC2 p.Pro557Arg (c.1670C>G) is ultra-rare (popmax 0.0911%, sas) (gnomAD).

What do computational predictors say about TANC2 p.Pro557Arg (c.1670C>G)?

AlphaMissense predicts ambiguous (score 0.5535) — an in-silico prediction, not a clinical call.

TANC2 p.Pro557Arg

Q: What condition is associated with TANC2 p.Pro557Arg (c.1670C>G)?

TANC2 p.Pro557Arg (c.1670C>G) is associated with intellectual developmental disorder with autistic features and language delay, with or without seizures (ClinVar).

c.1670C>G · VCV3892598

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5535 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0911%, sas)

Conditions

intellectual developmental disorder with autistic features and language delay, with or without seizures

Computational evidence

Protein change
AlphaMissense	0.5535	ambiguous
REVEL	0.453	indeterminate
SaProt	LLR -9.49	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.97, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 345 kb · p 0.00018 · 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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P483R vs ClinVar P557R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0911% South Asian · 83/91,086 alleles

Filtering AF 0.0752% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0694%

Overall 0.00533% 86/1,613,816 alleles · ultra-rare exomes 83/1,461,690 · genomes 3/152,126 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0911%	1,097
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0032%	31,234

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: TANC2
Protein: p.Pro557Arg
Coding: c.1670C>G
MANE Select: NM_001394998
Type: single nucleotide variant
Location: chr17:63340195 (GRCh38)
Gene constraint: LOEUF 0.17 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.92

Full TANC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual developmental disorder with autistic features and language delay, with or without seizures — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TANC2 p.Arg1516Gln Uncertain significance ★★ ⚠ same condition
TANC2 p.Arg1741Gln Uncertain significance ★★ ⚠ same condition
TANC2 p.Arg834Cys Uncertain significance ★★ ⚠ same condition
TANC2 p.Asp54Asn Uncertain significance ★★ ⚠ same condition
TANC2 p.Ile615Thr Uncertain significance ★★ ⚠ same condition
TANC2 p.Pro1895Thr Uncertain significance ★★ ⚠ same condition
TANC2 p.Ser1634Gly Uncertain significance ★★ ⚠ same condition
TANC2 p.Ser36Arg 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/tanc2-p-pro557arg (accessed [today's date]).

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