Is TNC p.Ser616Arg (c.1848C>A) pathogenic?

TNC p.Ser616Arg (c.1848C>A) is classified Uncertain significance in TNC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-19). AlphaMissense: likely benign (0.2509); Very rare (popmax 0.00881%, sas).

How common is TNC p.Ser616Arg (c.1848C>A) in the general population?

TNC p.Ser616Arg (c.1848C>A) is very rare (popmax 0.00881%, sas) (gnomAD).

What do computational predictors say about TNC p.Ser616Arg (c.1848C>A)?

AlphaMissense predicts likely benign (score 0.2509) — an in-silico prediction, not a clinical call.

TNC p.Ser616Arg

c.1848C>A · rs563361695 · VCV2555992

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2509 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00881%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2509	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -6.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -13
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.8 · regional, not allelic
Overall
CADD	0.001	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 0.00881% South Asian · 8/90,856 alleles

Filtering AF 0.00547% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00507%

Overall 0.00565% 91/1,611,132 alleles · very rare exomes 85/1,458,794 · genomes 6/152,338 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00881%	11,357
European (non-Finnish)	0.00671%	14,908
Remaining individualsnot grpmax-eligible	0.00481%	20,777
African / African-American	0.00133%	74,998

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.Ser616Arg
Coding: c.1848C>A
MANE Select: NM_002160
dbSNP: rs563361695
Type: single nucleotide variant
Location: chr9:115085883 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB
Residue 616: the egf-like 15 domain

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

Similar variants

TNC p.Ser616Gly Uncertain significance ★ ⚠ same residue
TNC p.Arg1127Trp Uncertain significance ★★ ⚠ same type
TNC p.Arg608Cys Uncertain significance ★★ ⚠ same type
TNC p.Arg669His Uncertain significance ★★ ⚠ same type
TNC p.Arg747Trp Uncertain significance ★★ ⚠ same type
TNC p.Asn507Lys Uncertain significance ★★ ⚠ same type
TNC p.Asp2059Glu Uncertain significance ★★ ⚠ same type
TNC p.Asp831Asn 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/tnc-p-ser616arg (accessed [today's date]).

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