Is SHC1 p.Pro47Ser (c.139C>T) pathogenic?

SHC1 p.Pro47Ser (c.139C>T) is classified Uncertain significance in SHC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-06). AlphaMissense: likely benign (0.1232); Ultra-rare (popmax 0.0227%, afr).

How common is SHC1 p.Pro47Ser (c.139C>T) in the general population?

SHC1 p.Pro47Ser (c.139C>T) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about SHC1 p.Pro47Ser (c.139C>T)?

AlphaMissense predicts likely benign (score 0.1232) — an in-silico prediction, not a clinical call.

SHC1 p.Pro47Ser

c.139C>T · rs563504056 · VCV2380017

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1232 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1232	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -6.49	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 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 368 bp · p 0.81 · regional, not allelic
Overall
CADD	23.1	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 0.0227% African / African-American · 17/74,774 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.00119% 19/1,602,954 alleles · ultra-rare exomes 7/1,450,630 · genomes 12/152,324 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,398
Remaining individualsnot grpmax-eligible	0.00161%	62,022
European (non-Finnish)	8.51e-05%	1,175,076

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: SHC1
Protein: p.Pro47Ser
Coding: c.139C>T
MANE Select: NM_001130040
dbSNP: rs563504056
Type: single nucleotide variant
Location: chr1:154970388 (GRCh38)
Gene constraint: LOEUF 0.705 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.24 · 11 PDB
Residue 47: the 'disordered' 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-pro47ser (accessed [today's date]).

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