Is TNC p.Phe1012Ser (c.3035T>C) pathogenic?

TNC p.Phe1012Ser (c.3035T>C) is classified Uncertain significance in TNC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-09). AlphaMissense: likely pathogenic (0.8188); Ultra-rare (popmax 0.0267%, amr).

How common is TNC p.Phe1012Ser (c.3035T>C) in the general population?

TNC p.Phe1012Ser (c.3035T>C) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

What do computational predictors say about TNC p.Phe1012Ser (c.3035T>C)?

AlphaMissense predicts likely pathogenic (score 0.8188) — an in-silico prediction, not a clinical call.

TNC p.Phe1012Ser

c.3035T>C · VCV3971268

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8188 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8188	likely pathogenic
REVEL	0.408	indeterminate
SaProt	LLR -12.28	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.1	GERP -0.59, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.8 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0267% Admixed American · 16/60,012 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00105% 17/1,614,090 alleles · ultra-rare exomes 17/1,461,860 · genomes 0/152,230 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,751
European (non-Finnish)	8.47e-05%	1,180,006

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.Phe1012Ser
Coding: c.3035T>C
MANE Select: NM_002160
Type: single nucleotide variant
Location: chr9:115073782 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.48 · 21 PDB
Residue 1012: the fibronectin type-iii 5 domain

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

Similar variants

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
TNC p.Asp971Asn 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-phe1012ser (accessed [today's date]).

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