Is TNC p.Asn441Ser (c.1322A>G) pathogenic?

TNC p.Asn441Ser (c.1322A>G) is classified Benign/Likely benign in TNC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2022-04-01). AlphaMissense: likely benign (0.0503); Rare (popmax 0.506%, afr); Associated with autosomal dominant nonsyndromic hearing loss 56.

What condition is associated with TNC p.Asn441Ser (c.1322A>G)?

TNC p.Asn441Ser (c.1322A>G) is associated with autosomal dominant nonsyndromic hearing loss 56 (ClinVar).

How common is TNC p.Asn441Ser (c.1322A>G) in the general population?

TNC p.Asn441Ser (c.1322A>G) is rare (popmax 0.506%, afr) (gnomAD).

What do computational predictors say about TNC p.Asn441Ser (c.1322A>G)?

AlphaMissense predicts likely benign (score 0.0503) — an in-silico prediction, not a clinical call.

TNC p.Asn441Ser

c.1322A>G · rs142220270 · VCV723838

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0503 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.506%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant nonsyndromic hearing loss 56

Computational evidence

Protein change
AlphaMissense	0.0503	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -7.15	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 -8
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.8 · regional, not allelic
Overall
CADD	0.02	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 0.506% African / African-American · 379/74,842 alleles

Filtering AF 0.464% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.448%

Overall 0.066% 1,065/1,613,590 alleles · rare exomes 806/1,461,778 · genomes 259/151,812 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.506%	197
South Asian	0.482%	207
Middle Eastern	0.182%	551
Remaining individualsnot grpmax-eligible	0.0576%	1,736
Admixed American	0.0383%	2,608
East Asian	0.0201%	4,982
European (non-Finnish)	0.0142%	7,065
Finnishnot grpmax-eligible	0.00156%	63,932

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: TNC
Protein: p.Asn441Ser
Coding: c.1322A>G
MANE Select: NM_002160
dbSNP: rs142220270
Type: single nucleotide variant
Location: chr9:115086409 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB
Residue 441: the egf-like 10 domain

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

Disease context

autosomal dominant nonsyndromic hearing loss 56 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TNC p.Arg669His Uncertain significance ★★ ⚠ same condition
TNC p.Arg747Trp Uncertain significance ★★ ⚠ same condition
TNC p.Asp971Asn Uncertain significance ★★ ⚠ same condition
TNC p.Ile1148Val Uncertain significance ★★ ⚠ same condition
TNC p.Thr1095Ile Uncertain significance ★★ ⚠ same condition
TNC p.Thr1138Met Uncertain significance ★★ ⚠ same condition
TNC p.Thr987Met Uncertain significance ★★ ⚠ same condition
TNC p.Val1898Ile 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/tnc-p-asn441ser (accessed [today's date]).

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