Is TNC p.Ser1125Arg (c.3375C>A) pathogenic?

TNC p.Ser1125Arg (c.3375C>A) is classified Benign/Likely benign in TNC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-11-25). AlphaMissense: likely benign (0.2397); Low-frequency (popmax 2.74%, afr); Associated with autosomal dominant nonsyndromic hearing loss 56.

What condition is associated with TNC p.Ser1125Arg (c.3375C>A)?

TNC p.Ser1125Arg (c.3375C>A) is associated with autosomal dominant nonsyndromic hearing loss 56 (ClinVar).

How common is TNC p.Ser1125Arg (c.3375C>A) in the general population?

TNC p.Ser1125Arg (c.3375C>A) is low-frequency (popmax 2.74%, afr) (gnomAD).

What do computational predictors say about TNC p.Ser1125Arg (c.3375C>A)?

AlphaMissense predicts likely benign (score 0.2397) — an in-silico prediction, not a clinical call.

TNC p.Ser1125Arg

c.3375C>A · rs61737056 · VCV789778

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2397 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.74%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant nonsyndromic hearing loss 56

Computational evidence

Protein change
AlphaMissense	0.2397	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	LLR -9.49	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 4.5	GERP -0.09, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.8 · regional, not allelic
Overall
CADD	17.49	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 2.74% African / African-American · 2,053/75,024 alleles

Filtering AF 2.64% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.6%

Overall 0.138% 2,230/1,614,138 alleles · low-frequency exomes 1,077/1,461,888 · genomes 1,153/152,250 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.74%	37
Remaining individualsnot grpmax-eligible	0.139%	718
Admixed American	0.107%	938
Middle Eastern	0.066%	1,516
European (non-Finnish)	0.00178%	56,191
South Asian	0.0011%	91,076

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.Ser1125Arg
Coding: c.3375C>A
MANE Select: NM_002160
dbSNP: rs61737056
Type: single nucleotide variant
Location: chr9:115064759 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB
Residue 1125: the fibronectin type-iii 6 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-ser1125arg (accessed [today's date]).

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