Is SHC1 p.Asp467Glu (c.1401T>A) pathogenic?

SHC1 p.Asp467Glu (c.1401T>A) is classified Uncertain significance in SHC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-05). AlphaMissense: ambiguous (0.4612); Very rare (popmax 0.00382%, nfe).

How common is SHC1 p.Asp467Glu (c.1401T>A) in the general population?

SHC1 p.Asp467Glu (c.1401T>A) is very rare (popmax 0.00382%, nfe) (gnomAD).

What do computational predictors say about SHC1 p.Asp467Glu (c.1401T>A)?

AlphaMissense predicts ambiguous (score 0.4612) — an in-silico prediction, not a clinical call.

SHC1 p.Asp467Glu

c.1401T>A · rs777523473 · VCV2495334

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4612 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00382%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4612	ambiguous
REVEL	0.697	pathogenic-leaning
SaProt	LLR -4.38	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP -0.51, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 3,939 bp · p 0.56 · regional, not allelic
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM D466E vs ClinVar D467E) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00382% European (non-Finnish) · 45/1,179,114 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00298% 48/1,612,918 alleles · very rare exomes 43/1,460,714 · genomes 5/152,204 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00382%	26,203
African / African-American	0.00267%	37,447
Remaining individualsnot grpmax-eligible	0.0016%	62,442

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: SHC1
Protein: p.Asp467Glu
Coding: c.1401T>A
MANE Select: NM_001130040
dbSNP: rs777523473
Type: single nucleotide variant
Location: chr1:154965768 (GRCh38)
Gene constraint: LOEUF 0.705 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.24 · 11 PDB
Residue 466 UniProt numbering: the 'ch1' region

Full SHC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SHC1 p.Ala373Thr Uncertain significance ★ ⚠ same type
SHC1 p.Ala373Val Uncertain significance ★ ⚠ same type
SHC1 p.Ala39Val Uncertain significance ★ ⚠ same type
SHC1 p.Arg146Pro Uncertain significance ★ ⚠ same type
SHC1 p.Arg207Thr Uncertain significance ★ ⚠ same type
SHC1 p.Arg214Cys Uncertain significance ★ same type
SHC1 p.Arg311His Uncertain significance ★ ⚠ same type
SHC1 p.Arg369Trp 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/shc1-p-asp467glu (accessed [today's date]).

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