Is SCN7A p.Tyr287Cys (c.860A>G) pathogenic?

SCN7A p.Tyr287Cys (c.860A>G) is classified Uncertain significance in SCN7A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-05). AlphaMissense: likely benign (0.096); Ultra-rare (popmax 0.0494%, mid).

How common is SCN7A p.Tyr287Cys (c.860A>G) in the general population?

SCN7A p.Tyr287Cys (c.860A>G) is ultra-rare (popmax 0.0494%, mid) (gnomAD).

What do computational predictors say about SCN7A p.Tyr287Cys (c.860A>G)?

AlphaMissense predicts likely benign (score 0.096) — an in-silico prediction, not a clinical call.

SCN7A p.Tyr287Cys

c.860A>G · VCV3438311

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.096 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.096	likely benign
REVEL	0.35	indeterminate
SaProt	LLR -9.52	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.16	GERP -4.8, phastCons 0.001
Regional constraint	o/e 1.04	unconstrained · MANE · 72 kb · p 0.11 · regional, not allelic
Overall
CADD	10.57	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 0.0494% Middle Eastern · 3/6,068 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00717%

Overall 0.00198% 32/1,613,706 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0494%	2,023
Remaining individualsnot grpmax-eligible	0.00961%	10,410
Admixed American	0.00333%	29,993
European (non-Finnish)	0.0017%	58,991
African / African-American	0.00133%	74,924

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: SCN7A
Protein: p.Tyr287Cys
Coding: c.860A>G
MANE Select: NM_002976
Type: single nucleotide variant
Location: chr2:166465792 (GRCh38)
Gene constraint: LOEUF 1.124 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.18 · 2 PDB
Residue 287: an α-helix; a disulfide bond

Full SCN7A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SCN7A p.Val187Ile Uncertain significance ★★ ⚠ same type
SCN7A c.3028-9A>T Benign ★★ same type
SCN7A p.Ala1282Val Benign ★★ same type
SCN7A p.Ala1313= Benign/Likely benign ★★ same type
SCN7A p.Ala456Gly Likely benign ★★ same type
SCN7A p.Ala818Ser Likely benign ★★ same type
SCN7A p.Arg1106Gln Likely benign ★★ same type
SCN7A p.Arg1516Lys Likely benign ★★ 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/scn7a-p-tyr287cys (accessed [today's date]).

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